Synthesis of diaryl ethers, diaryl sulfides, heteroaryl ethers and heteroaryl sulfides under microwave dielectric heating

Article abstract of DOI:10.1055/s-2005-865321

This paper describes the synthesis of diaryl ethers and sulfides by utilizing microwave heating methodology. The methodology is shown to be rapid and efficient for the coupling of phenols or thiophenol with electron-deficient aryl halides through a S_NAr reaction. The scope of the protocol can be expanded to six-membered heterocycles bearing a hydroxyl group as well as to the reaction of 2-pyrimidinethiol with mildly activated aryl halides, providing heteroaryl ethers and sulfides, respectively. The advantages of the present method include the wide substrate scope, the obviation of metal catalysts, ease of product isolation, and high purity of products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865321

PAPER
1305
Synthesis of Diaryl Ethers, Diaryl Sulfides, Heteroaryl Ethers and Heteroaryl
Sulfides under Microwave Dielectric Heating
Synthesisof
D
e
iaryl
E
ther
n
g
d
H
eteroaryl
Ether
L
s/Sulfide
s
i, Qingqing Meng, Huansheng Chen, Zhiming Li, Quanrui Wang,* Fenggang Tao
Department of Chemistry, Fudan University, 200433 Shanghai, P. R. China
Fax +86(21)65641740; E-mail: qrwang@fudan.edu.cn
Received 17 September 2004; revised 3 February 2005
with aryl halides or arylboronic acids as electrophiles,
Abstract: This paper describes the synthesis of diaryl ethers and
sulfides by utilizing microwave heating methodology. The method-
ology is shown to be rapid and efficient for the coupling of phenols
or thiophenol with electron-deficient aryl halides through a SNAr re-
with efforts particularly being concentrated on copper4a–4e
and palladium4f–4h salts. The second strategy seems to be
more flexible in that activating groups on aryl halides are
action. The scope of the protocol can be expanded to six-membered not required, but the reactivity order is still typical of that
heterocycles bearing a hydroxyl group as well as to the reaction of
for nucleophiles despite the presence of the metal salts,
2-pyrimidinethiol with mildly activated aryl halides, providing het-
however, harsher reaction conditions are required.
eroaryl ethers and sulfides, respectively. The advantages of the
The use of microwave heating as a tool for organic synthe-
sis has been a very promising area and microwave-pro-
moted reactions have provided the focus for many recent
research activities.7,8 The advantages of the microwave
method over conventional techniques include the much
shortened reaction time, more eco-friendly technique and,
in some cases, higher purity of final products than conven-
tional reactions. In our initial communication, we reported
a general microwave-assisted preparation of diaryl ethers
that constitutes a useful complement to the SNAr strategy.9
The microwave enhanced combination of phenols and
aryl halides are a desirable extension of other recently re-
ported diaryl ether synthesis techniques10 in which the
substrate scope was restricted to phenols containing no
strong electron-accepting groups. Moreover, the reported
procedure usually required a metal catalyst.
present method include the wide substrate scope, the obviation of
metal catalysts, ease of product isolation, and high purity of prod-
ucts.
Key words: dielectric heating, diaryl ether, diaryl sulfide, synthesis
The diaryl ether moiety is found in a variety of naturally
occurring and medicinally significant compounds and the
synthesis of this framework has aroused considerable in-
terest.1 The classic Ullmann ether synthesis from aryl ha-
lides and phenols provides one of the most direct methods
for the formation of a diaryl ether linkage,2 the reactivity
order is typical of that for nucleophilic substitution, de-
spite the presence of aryloxycopper(I) reagents ArOCu as
intermediates. Although the Ullmann ether synthesis is
not fully hampered by electron-donating groups, electron-
poor aryl halides proved to be superior substrates for ether
formation. There are some other limitations incurred with
the Ullmann ether synthesis, such as the need for harsh re-
action conditions and metal catalysts. As such, develop-
ment of improved conditions has received an ever-
increasing interests in recent years,3,4 and a need for devis-
ing widely applicable and operationally simple variations
toward the diaryl ether motif remains.
Significant alternatives to the Ullmann method5 may be
classified into two categories. One is the aromatic nucleo-
philic substitution reaction (SNAr) of activated aryl ha-
lides with phenols under basic conditions, especially at
positions ortho and para to the leaving group. Simple aryl
halides behave like vinylic halides, and an electron-at-
tracting group at the meta position does not produce evi-
dent activating effect. Sawyer has employed this strategy
for the assembly of diaryl ethers in the presence of stoi-
chiometric quantities of KF-alumina together with cata-
lytic quantities of 18-crown-6.6 The other useful strategy
involves catalytic metal salt mediated coupling of phenols
Heterocyclic analogs of diaryl ethers like Fluazifop-bu-
tyl,11 useful as an herbicide in agriculture, are also of
much synthetic interest, but reports about this can only oc-
casionally be found in the literature. In 1990, Hwang re-
ported the successful synthesis of phenyl pyridyl ethers
promoted by the fluoride ion.12 Brandsma and co-workers
have investigated the reaction of halogenated benzenes or
heterocycles with sodium alkoxides using CuBr as a cata-
lyst, by which a number of alkyl aryl and alkyl heteroaryl
ethers were formed.13 In addition, Wang has described the
synthesis of 8-quinolinyl ethers from 8-hydroxy quino-
lines and organic halides under PTC and dielectric heating
conditions, but only activated alkyl halides were exam-
ined.14 A similar procedure for rapid microwave-assisted
synthesis of several 2-hydroxyphenyl heteroaryl ethers
has been reported recently by Kumar.15
In the present paper, we wish to report the microwave-me-
diated synthesis of a range of diaryl ethers, diaryl sulfides,
heteroaryl ethers, and heteroaryl sulfides. It has been dem-
onstrated that under our conditions, electron-deficient,
electronically neutral as well as electron-rich phenols and
thiophenols, and also heterocyclic counterparts can suc-
cessfully be coupled with a variety of activated aryl ha-
lides in the absence of a metal catalyst. We have shown
SYNTHESIS 2005, No. 8, pp 1305–1313
x
x
.
x
x
.2
0
0
5
Advanced online publication: 19.04.2005
DOI: 10.1055/s-2005-865321; Art ID: F13304SS
© Georg Thieme Verlag Stuttgart · New York

1306
F. Li et al.
PAPER
that within a few minutes high conversion rates were ob- crowded, the desired reaction is completely hindered, thus
tained under microwave heating in comparison to hours even after 15 minutes the corresponding product cannot
with traditional methods, thereby increasing the substrate be detected from the reaction mixture (Table 1, entry 4).
scope of the methodology significantly.
Both guaiacol and 4-methoxyphenol react smoothly as the
substrate affording the respective product in high yield
(Table 1, entries 5–7).
The coupling of phenol with 4-fluorobenzonitrile was in-
vestigated in our initial foray. The reaction was performed
on a 10 mmol scale in an open vessel with heating.
DMSO, a typical dipolar aprotic organic solvent, was cho-
sen as the reaction medium due to its high dielectric con-
stant (e = 46.68 at 25 °C). We found that the reaction
proceeds rapidly under microwave irradiation (300 W) us-
ing 2 equivalents of anhydrous potassium carbonate as the
base and 96% yield of the coupled product 4-phenoxyben-
zonitrile was obtained in 5 minutes. To explore the solvent
scope, acetonitrile was also tested in this reaction, but it
proved to be deleterious, resulting in only a 40% conver-
sion after 10 minutes (GC) and 65% after 20 minutes.
Even after 30 minutes, the reaction does not reach com-
pletion. With its relatively high boiling point and a high
tan d value, DMSO was adopted as the solvent throughout
the present investigations.16 Microwave heating has re-
sulted in far shorter reaction times than traditional heating
for a great range of organic reactions though its nature is
not fully understood. The high temperature may account
for the prominent acceleration in the present SNAr reac-
tion.17
Table 1 Coupling of Phenols with Fluorobenzonitrile to Afford Aryl-
oxy-Substituted Benzonitrilea
OH
F
1'
1
1
O
1'
K2CO3/DMSO
MW
+
R1
R1
CN
CN
Entry R1
Position Reaction time Isolated yield
of CN
(min)
(%)
1
2
H
4¢
5
96
4-tert-Butyl
2-tert-Butyl
4¢
5
93
3
4¢
10
15
5
77
4
2,6-Di-tert-butyl
2-OMe
4¢
NRb
86
5
4¢
6
2-OMe
2¢
5
94
7
4-OMe
4¢
5
85
8
4-Cl
4¢
5
93
9
2-Cl-4-Ph
2,3,4,5,6-Cl5
4-CN
4¢
5
85
10
11
12
13
14
15
16
17
18
19
4¢
15
10
10
10
10
15
5
NRb
87
Synthesis of Aryloxybenzonitrile Using Fluoroben-
zonitrile
4¢
4-CN
2¢
98
Under our optimal microwave-promoted conditions, the
reaction of phenol and 4-fluorobenzonitrile gave almost a
quantitative yield of 4-phenoxybenzonitrile in only five
minutes (Table 1, entry 1). This indicates a dramatic re-
duction in reaction time when compared with convention-
al heating methodology.18 Thus, for example, under usual
heating conditions, the KF-Al2O3 catalyzed coupling of
phenols with 2- or 4-fluorobenzonitrile has been reported
to require 18–336 hours in refluxing acetonitrile and the
etherification of 2-hydroxybenzonitrile with 4-fluoroben-
zonitrile takes 36 hours to reach completion in DMSO at
140 °C.6
4-NO2
4¢
52c
62c
NRb
86
4-CF3
4¢
2-NO2
4¢
3-CF3
4¢
2-OMe
3¢
10
10
5
74
4-Cl
3¢
81
4-(Imidazol-1-yl)
2¢
98
a Fluoro-substituted benzonitrile (1 mmol), phenol (1–1.2), K2CO3 (2
mmol), DMSO (5 mL), using microwave power of 300 W. The tem-
perature is ramped to the boiling point of DMSO and held there for the
time indicated.
Both 2- and 4-fluorobenzonitrile work well for the prepa-
ration of aryloxybenzonitriles and a wide range of groups
at the phenol ring are tolerated in the present protocol,
with those having an electron-releasing group more fa-
vored. 4-(4-tert-Butylphenoxy)benzonitrile was obtained
in five minutes in 93% isolated yield from 4-tert-bu-
tylphenol and 4-fluorobenzonitrile (Table 1, entry 2). In-
terestingly, 4-fluorobenzonitrile can also be successfully
condensed with 2-tert-butylphenol, producing sterically
congested 4-(2-tert-butylphenoxy)benzonitrile in satis-
factory yield in ten minutes (Table 1, entry 3). This may
reflect the specific accelerating effect generated by micro-
wave heating,8c as sterically demanding groups are noto-
riously uncooperative under normal heating conditions.19
However, probably since 2,6-di-tert-butylphenol is too
b No reaction observed.
c Yield by GC.
For phenols containing a weak to mildly electron-with-
drawing group like -Cl or -Ph on the aromatic ring the re-
action proceeds with no difficulty to give the diaryl ether
in high to excellent yields (Table 1, entries 8 and 9) in
only five minutes. It is not surprising that no coupled
product could be obtained from pentachlorophenol even
after microwave irradiation for 15 minutes because the
combined effects of the five chloro atoms diminished the
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

PAPER
Synthesis of Diaryl Ethers/Sulfides and Heteroaryl Ethers/Sulfides
1307
OH
nucleophilicity of the aryloxy considerably (Table 1, en-
try 10).
F
+
F3C
CN
To explore the substrate scope of the reaction, we contin-
ued the study to encompass phenols containing a strong
electron-withdrawing group. This is of much interest con-
sidering electron-poor phenols behave sluggishly or are
ineffective in SNAr reactions under conventional heating
conditions. Thus, phenols having a cyano, nitro, or trifluo-
romethyl group were investigated and the results are
promising (Table 1, entries 11–16), although somewhat
prolonged reaction times (ten minutes) were required to
drive the reaction to completion. In the case of 4-cy-
anophenol the reaction with 2- or 4-fluorobenzonitrile
were run with no difficulty to give the coupled diaryl
ethers 4-(4¢-cyanophenoxy)benzonitrile and 4-(2¢-cy-
K2CO3/DMSO
MW
10 min
O
O
+
F3C
CN
F3C
COOH
62%
18%
Scheme 2
and hence the alkalinity of the solution is not strong
enough to destroy the hydrogen bond.
anophenoxy)benzonitrile in 87% and 98% yields, respec- On the other hand, when 3-trifluoromethylphenol was
tively (Table 1, entries 11 and 12). The reaction using subjected to reaction with 4-fluorobenzonitrile, the ex-
nitrophenol with 4-fluorobenzonitrile seems to be slightly pected 4-(3-trifluoromethylphenoxy)benzonitrile could
inconsistent (Table 1, entry 13). When 4-nitrophenol was be readily obtained in 86% yield in 5 minutes (Table 1,
allowed to react with 4-fluorobenzonitrile under micro- entry 16).
wave heating for 10 minutes, two more reaction products
were isolated besides the desired product 4-(4-nitrophen-
Next we were keen to know if a fluoro group at the meta
position on the benzonitrile ring could serve as a leaving
oxy)benzonitrile (52% yield), namely 4-(4-nitrophen-
group, and so we screened the reaction of 3-fluoroben-
oxy)benzoic acid (5.8%), presumably a hydrolyzed
zonitrile with guaiacol as well as 4-chlorophenol as repre-
product of the target molecule, and 4-(4¢-cyanophen-
sentatives of phenols possessing diverse groups. We were
oxy)benzonitrile (8.6%), which is likely to have formed
pleased to find that 3-fluorine substituted benzene reacted
by initial defluorohydroxylation of 4-fluorobenzonitrile
equally well under our microwave-DMSO protocol pro-
and subsequent coupling with itself (Scheme 1). To our
ducing the diaryl ethers in moderate to high yields
knowledge, 4-nitrophenol has only been rarely employed
(Table 1, entries 17 and 18).
for diaryl ether synthesis and in the reported procedure the
The wide range of functional group tolerance in this meth-
reaction did not reach completion affording low product
od was further evidenced by the reaction of 4-(imidazol-
yield.6
1-yl)phenol with 2-fluorobenzonitrile, producing 2-[4-
There was a similar occurrence when 4-fluorobenzonitrile
(imidazol-1-yl)]phenoxybenzonitrile in almost quantita-
was coupled with 4-trifluoromethylphenol. The reaction
tive yield (Table 1, entry 19).
was finished in 10 minutes producing a 62% yield of 4-(4-
trifluoromethylphenoxy)benzonitrile (GC) and 18% yield
of 4-(4-trifluoromethylphenoxy)benzoic acid (GC)
(Table 1, entry 14; Scheme 2). The precise factors that
govern the abnormal behavior in such instances are un-
Coupling of Phenols with 4-Bromobenzonitrile or 1-
Chloro-4-nitrobenzene
clear.
Having established that a fluorine atom on the benzene
In marked contrast, the reaction with 2-nitrophenol did ring works well as a leaving group for the diaryl ether syn-
not occur under our conditions (Table 1, entry 15). Steric thesis we were next interested in looking at the possibility
hindrance may be one reason, but here intramolecular hy- of using other kinds of substrates, in considering the fact
drogen bonding may also come into play. The solubility of that fluorobenzenes are generally more expensive than
potassium carbonate in DMSO is not sufficiently great their bromo and chloro counterparts. For this purpose, we
OH
F
+
O2N
CN
K2CO3/DMSO
MW
10 min
O
O
O
+
+
CO2H NC
O2N
CN O2N
CN
8.6%
52%
5.8%
Scheme 1
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

1308
F. Li et al.
PAPER
employed the electron-deficient 4-bromobenzonitrile and Table 3 Coupling of Thiophenol with Electron-Deficient Aryl Ha-
lidesa
1-chloro-4-nitrobenzene as substrates to couple with phe-
nols bearing different functional groups. As shown in
1'
1
SH
X
1'
S
1
K2CO3/DMSO
MW
+
R2
R2
Table 2, under microwave irradiation for a couple of min-
utes, both substrates reacted with either electron-rich or
electron-poor phenols to produce the expected diaryl
ethers in moderate to good yield (Table 2, entries 1–6).
The utility of the strategy is further demonstrated by entry
7, where 1-chloro-4-nitrobenzene successfully coupled
with 4-nitrophenol leading to 4,4¢-dinitrodiphenyl ether in
83% yield after microwave heating for ten minutes. It
should be recalled that the results using 4-nitrophenol as a
reaction partner in diaryl ether synthesis is generally less
satisfactory under conventional classical heating.
X = F, Cl, Br
Entry
X
R2
Reaction time (min) Yieldb (%)
1
2
3
F
2¢-CN
5
10
10
91
83
78
Br
Cl
4¢-CN
4¢-NO2
a Aryl halide (1 mmol), thiophenol (1–1.2 mmol), K2CO3 (2 mmol),
DMSO (5 mL), using microwave power of 300 W. The temperature
is ramped to the boiling point of DMSO and held there for the time
indicated.
Table 2 Coupling of Phenols to 4-Bromobenzonitrile or 1-Chloro-
4-nitrobenzenea
b Yields are given for isolated, purified compounds.
1'
X
1
OH
1
O
1'
K2CO3/DMSO
MW
+
R2
R2
R1
R1
our general protocol further. Our study was directed to-
ward introducing an aryloxy group onto some heterocy-
clic compounds. In comparison to the methods for
assembling diaryl ethers such a topic remains a relatively
unexplored field.14,15 As we have stated, aryloxy-substi-
tuted heterocycles are of biological significance. There is,
therefore, a distinct need for useful methods that allow the
efficient transformation of an OH group to an aryloxy
group on heterocyclic rings.
X = Cl, Br
Entry R1
X
R2
Reaction time Yieldb
(min)
10
10
10
15
5
(%)
78
87
67
65
99
95
83
1
2
3
4
5
6
7
2-OMe
4-Cl
Br
Br
Br
Br
Cl
Cl
Cl
4¢-CN
4¢-CN
4¢-CN
4¢-CN
4¢-NO2
4¢-NO2
4¢-NO2
3-CF3
4-CN
2-OMe
4-CN
4-NO2
Much to our delight, all the hydroxy-containing heterocy-
cles at hand can couple with a range of electron-deficient
aryl halides and the results are garnered in Table 4. The
investigations demonstrated that the reaction with suit-
ably activated aryl halides results in the formation of the
corresponding aryloxylated heterocycles. The reaction
conditions are almost the same as for phenols.
5
10
a Aryl halide (1 mmol), phenol (1–1.2 mmol), of K2CO3 (2 mmol),
DMSO (5 mL), using microwave power of 300 W. The temperature is
ramped to the boiling point of DMSO and held there for the time in-
dicated.
When 7-hydroxy-4-methylcoumarin reacted with 2-fluo-
robenzonitrile, the desired product was obtained in 86%
yield (Table 4, entry 1). Likewise, 8-hydroxyquinoline
can be coupled with different kinds of aryl halides, yield-
ing the aryloxylated compounds in moderate to high
yields after 5–10 minutes of microwave heating (Table 4,
entries 2–5). We can see from entry 5 that 3-fluoroben-
zonitrile can also be coupled with 8-hydroxyquinoline,
but this proved less reactive affording lower product
yield.
b Yields are given for isolated, purified compounds.
Synthesis of Diaryl Sulfides20
In an attempt to widen the scope of the microwave heating
protocol we next examined the behavior of thiophenol in
place of phenols. We found that thiophenol can also be
coupled with an electron-deficient aryl halide yielding the
diaryl sulfide in moderate to high yields under our stan-
dard microwave irradiation conditions, as exemplified by
the reaction with 2-fluorobenzonitrile, 4-bromobenzoni-
trile, and 1-chloro-4-nitrobenzene. The results are pre-
sented in Table 3.
The OH group may also reside on the nitrogen-containing
ring of quinoline systems, although the reaction seems to
call for an electron-donating group like methyl to enhance
the reactivity of the involved heterocyclic O-nucleophile.
This was illustrated by the reaction of 2-methyl-4-quino-
linol with activated aryl halides (Table 4, entries 6–8).
Comparable results were also obtained by using 6-methyl-
3-pyridinol affording the expected products in satisfacto-
ry yields (Table 4, entries 9–12). Our investigation sug-
gests that the reaction using OH-substituted six-
membered heterocycles or fused analogs works equally
well with only moderate sensitivity towards electronic ef-
fects and steric hindrance.
Expansion of the Substrate Scope of the Reaction to
Incorporate Hydroxy-Substituted Heterocycles
Due to the ease of construction of simple diaryl ethers un-
der microwave heating, we decided to widen the scope of
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

PAPER
Synthesis of Diaryl Ethers/Sulfides and Heteroaryl Ethers/Sulfides
1309
Table 4 Coupling of Hydroxy-Containing Heterocycles with Electron-Deficient Aryl Halidesa
Entry
1
Het-OH
Aryl halide
Product
Reaction time (min) Yieldb (%)
5
86
O
O
OH
F
CN
O
O
O
CN
2
5
91
F
OH
N
CN
N
O
NC
3
4
5
6
10
5
78
94
64
75
Br
Cl
F
OH
OH
OH
OH
N
N
N
N
N
N
CN
O
O
O
O
CN
NO2
NO2
10
10
CN
CN
F
CN
N
N
NC
7
8
9
10
10
5
62
80
74
OH
Br
Cl
CN
N
N
O
O
CN
N
OH
NO2
NO2
N
CN
N
F
OH
O
CN
N
10
11
10
10
78
70
Br
Cl
N
N
N
OH
OH
O
O
CN
CN
N
N
NO2
NO2
12
15
67
CN
CN
N
F
OH
O
a Aryl halide (1 mmol), hydroxylated heterocycle (1–1.2 mmol), K2CO3 (2 mmol), DMSO (5 mL), using a microwave power of 300 W. The
temperature is ramped to the boiling point of DMSO and held there for the time indicated.
b Yields are given for isolated, purified compounds.
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

1310
F. Li et al.
PAPER
were carried out in a domestic microwave oven that had been mod-
ified according to Mingos and Baghurst’s technique to allow safe
refluxing without a build-up of pressure and allow for the escape of
volatiles.21 The upper wall of the oven was holed for connecting the
condenser and the reaction vessel. The key lay in that the water-
cooled reflux condenser was located completely outside the micro-
wave cavity since the circulating water coolant could absorb micro-
waves strongly. The reactions were monitored by TLC coated with
silica gel. Separations and purifications (if necessary) were per-
formed by flash chromatography on silica gel (200–300 mesh) col-
umns. All new compounds were characterized by 1H and 13C NMR
spectroscopy, MS spectroscopy, and elemental analyses.
Synthesis of 2-Arylthio-Substituted Pyrimidines
Finally, we extended the protocol to the synthesis of phe-
nylthio-substituted pyrimidines from which interesting bi-
ological activities are solicited. Thus, we screened the
reaction of 2-pyrimidinethiol with the following three aryl
halides: 2-fluorobenzonitrile, 4-bromobenzonitrile, and 1-
chloro-4-nitrobenzene. Again, its reaction proved to be
quite successful despite the combined unfavorable elec-
tron-withdrawing effects of two pyridine-like nitrogen at-
oms. The respective 2-arylthio substituted pyrimidines
were formed in moderate yields (Table 5).
Microwave-Assisted Reactions; General Procedure
An aryl halide (ArX, 10 mmol), phenol, thiophenol, or hydroxylated
heterocycle (Het-OH) (10–12 mmol) and K2CO3 (20 mmol) were
sequentially added to DMSO (50 mL). The reaction was found to be
not sensitive to air and moisture, hence there was no need for an in-
ert atmosphere. Using microwave power of 300 W the temperature
was ramped from r.t. to the bp of DMSO, which took 30–40 s, and
was then held there for 5–15 min. A blast shield was used for pro-
tection. After completion of the reaction, it was cooled to r.t., put
into ice water and stirred for 30 min to precipitate the product. Fil-
tration of the precipitation followed by washing with distilled water
afforded the desired products. In cases where further purification
was required, recrystallization was performed.
Table 5 Coupling of 2-Mercaptopyrimidine to Electron-Deficient
Aryl Halidesa
N
SH
X
N
S
K2CO3/DMSO
MW
+
R
R
N
N
Entry
X
F
R
Reaction time (min) Yieldb (%)
1
2
3
2-CN
4-CN
4-NO2
10
10
10
87
80
78
Br
Cl
4-Phenoxybenzonitrile (Table 1, entry 1)
Yield: 96%; white solid; mp 45–46 °C.
1H NMR (DMSO-d6): d = 7.80 (dd, J = 6.8, 2.1 Hz, 2 H), 7.48 (m,
2 H), 7.28 (m, 1 H), 7.14 (m, 2 H), 7.10 (d, J = 6.8 Hz, 2 H).
GC-MS: m/z = 195 (M+).
a Aryl halide (1 mmol), 2-pyrimidinethiol (1–1.2 mmol), K2CO3 (2
mmol), DMSO (5 mL), using a microwave power of 300 W. The tem-
perature is ramped to the boiling point of DMSO and held there for 10
min.
b Yields are given for isolated, purified compounds.
4-(4-tert-Butylphenoxy)benzonitrile (Table 1, entry 2)
Yield: 93%; white solid; mp 89–90 °C.
1H NMR (DMSO-d6): d = 7.83 (d, J = 8.6 Hz, 2 H), 7.48 (d, J = 8.6
Hz, 2 H), 7.08–7.06 (m, 4 H), 1.31 (s, 9 H, t-Bu).
GC-MS: m/z = 251 (M+).
In conclusion, we have reported in this paper a useful
method for the rapid preparation of diaryl ethers. The
electron-deficient phenols are shown to be well tolerated
in the coupling process. The method has been extended to
include the synthesis of diaryl sulfides, heteroaryl-aryl
ethers and heteroaryl-aryl sulfides, while it was observed
that a meta-cyano group in 3-fluorobenzonitrile produces
a similar activating effect. Furthermore, the simplicity of
this short and clean procedure and generality along with
the satisfactory yields render this method particularly at-
tractive. The eradication of any catalysts, especially the
heavy metals from the reaction offers another advantage
since their contamination of the product is always undesir-
able and the purification procedure as well as their prepa-
ration can be very costly. The presence of a diverse range
of substituents and functional groups in the products sug-
gests also an excellent opportunity to acquire many other
derivatives from these initial compounds. The present
protocol represents an operationally simple substitute for
conventional heating methods.
4-(2-tert-Butylphenoxy)benzonitrile (Table 1, entry 3)
Yield: 77%; white solid; mp 101–102 °C.
1H NMR (DMSO-d6): d = 7.81 (d, J = 8.7 Hz, 2 H), 7.45 (s, 1 H),
7.26 (m, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 2 H),
6.92 (m, 1 H), 1.31 (s, 9 H, t-Bu).
GC-MS: m/z = 251 (M+).
4-(2-Methoxyphenoxy)benzonitrile (Table 1, entry 5)
Yield: 86%; white solid; mp 90–91 °C.
1H NMR (DMSO-d6): d = 7.78 (dd, J = 6.8, 2.1 Hz, 2 H), 7.31 (t,
J = 7.3 Hz, 1 H), 7.24–7.17 (m, 2 H), 7.03 (t, J = 1.0 Hz, 1 H), 6.94
(dd, J = 6.8, 2.1 Hz, 2 H), 3.72 (s, 3 H, OCH3).
GC-MS: m/z = 225 (M+).
2-(2-Methoxyphenoxy)benzonitrile (Table 1, entry 6)
Yield: 94%; white solid; mp 79–80 °C.
1H NMR (DMSO-d6): d = 7.86–7.82 (m, 1 H), 7.57 (m, 1 H), 7.32–
7.29 (m, 1 H), 7.25–7.18 (m, 3 H), 7.04 (t, J = 1.0 Hz, 1 H), 6.63 (d,
J = 8.5 Hz, 1 H), 3.74 (s, 3 H, OCH3).
All materials were of commercial quality and were used as received.
The product purities were determined by GC-MS analysis. GC-MS
data was acquired on a TOP series GC8000 with a FINNIGAN-
VOYAGER mass selective detector. NMR data were acquired on a
Bruker 500 or a Varian 400 spectrometer. 1H and 13C NMR chemi-
cal shifts (d) are reported in ppm relative to TMS as internal stan-
dard. Coupling constants (J) are given in Hz. The elemental
analyses for C, H, and N were performed on a Carlo Erba 1106 ele-
mental analyzer. Melting points were uncorrected. All reactions
GC-MS: m/z = 225 (M+).
4-(4-Methoxyphenoxy)benzonitrile (Table 1, entry 7)
Yield: 85%; white solid; mp 108–109 °C.
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

PAPER
Synthesis of Diaryl Ethers/Sulfides and Heteroaryl Ethers/Sulfides
1311
1H NMR (DMSO-d6): d = 7.81 (d, J = 8.8 Hz, 2 H), 7.12–7.10 (dd,
J = 7.0, 2.1 Hz, 2 H), 7.03–7.01 (m, 4 H), 3.78 (s, 3 H, OCH3).
2-Methoxy-4¢-nitrodiphenyl Ether (Table 2, entry 5)
Yield: 99%; primrose yellow solid; mp 101–102 °C.
GC-MS: m/z = 225 (M+).
1H NMR (DMSO-d6): d = 8.21 (dd, J = 7.1, 2.3 Hz, 2 H), 7.30–7.27
(m, 1 H), 7.24–7.21 (m, 2 H), 7.06 (d, J = 1.0 Hz, 1 H), 7.00–6.97
(dd, J = 7.1, 2.3 Hz, 2 H), 3.73 (s, 3 H, OCH3).
4-(4-Chlorophenoxy)benzonitrile (Table 1, entry 8)
Yield: 93%; white solid; mp 81–82 °C.
1H NMR (DMSO-d6): d = 7.86 (dd, J = 6.8, 2.2 Hz, 2 H), 7.52 (dd,
J = 6.7, 2.3 Hz, 2 H), 7.21–7.10 (m, 4 H).
GC-MS: m/z = 245 (M+).
4-(4-Nitrophenoxy)benzonitrile (Table 2, entry 6)
Yield: 95%; yellow solid; mp 154–155 °C.
1H NMR (DMSO-d6): d = 8.31 (d, J = 9.2 Hz, 2 H), 7.96 (d, J = 8.8
Hz, 2 H), 7.36–7.26 (m, 4 H).
GC-MS: m/z = 229 (M+).
4-(2-Chloro-4-phenylphenoxy)benzonitrile (Table 1, entry 9)
Yield: 85%; white solid; mp 100–101 °C.
GC-MS: m/z = 240 (M+).
1H NMR (DMSO-d6): d = 7.96 (d, J = 2.2 Hz, 1 H), 7.87 (d, J = 8.9
Hz, 2 H), 7.76–7.73 (m, 3 H), 7.50–7.48 (m, 2 H), 7.43–7.41 (m, 2
H), 7.12 (d, J = 8.9 Hz, 1 H).
4,4¢-Dinitrodiphenyl Ether (Table 2, entry 7)
Yield: 83%; pale yellow solid; mp138–139 °C.
GC-MS: m/z = 305 (M+).
1H NMR (DMSO-d6): d = 8.36–8.31 (m, 4 H), 7.40–7.35 (m, 4 H).
GC-MS: m/z = 260 (M+).
4-(4-Cyanophenoxy)benzonitrile (Table 1, entry 11)
Yield: 87%; white solid; mp 179–180 °C.
1H NMR (DMSO-d6): d = 7.93 (d, J = 8.7 Hz, 4 H), 7.28 (d, J = 8.7
Hz, 4 H).
2-Phenylthiobenzonitrile (Table 3, entry 1)
Yield: 91%; white solid; mp 57–58 °C.
1H NMR (DMSO-d6): d = 7.92 (dd, J = 7.7, 1.0 Hz, 1 H), 7.65 (t,
J = 1.1 Hz, 1 H), 7.48–7.45 (m, 6 H), 7.24 (d, J = 8.0 Hz, 1 H).
GC-MS: m/z = 220 (M+).
GC-MS: m/z = 211 (M+).
2-(4-Cyanophenoxy)benzonitrile (Table 1, entry 12)
Yield: 98%; white solid; mp 90–91 °C.
1H NMR (DMSO-d6): d = 8.00–7.92 (m, 3 H), 7.77 (t, J = 0.7 Hz, 1
H), 7.44 (m, 1 H), 7.29–7.24 (m, 3 H).
4-Phenythiobenzonitrile (Table 3, entry 2)
Yield: 83%; white solid; mp 52–53 °C.
1H NMR (DMSO-d6): d = 7.72 (dd, J = 8.7, 3.0 Hz, 2 H), 7.54 (m,
2 H), 7.50 (m, 3 H), 7.24 (dd, J = 8.7, 3.0 Hz, 2 H).
GC-MS: m/z = 220 (M+).
GC-MS: m/z = 211 (M+).
4-(3-Trifluoromethylphenoxy)benzonitrile (Table 1, entry 16)
Yield: 86%; white solid; mp 55–56 °C.
1H NMR (DMSO-d6): d = 7.92–7.88 (m, 2 H), 7.70–7.65 (m, 2 H),
7.54–7.48 (m, 2 H), 7.21–7.18 (m, 2 H).
4-Nitrodiphenyl Sulfide (Table 3, entry 3)
Yield: 78%; yellow solid; mp 56–57 °C.
1H NMR (DMSO-d6): d = 8.13 (dd, J = 9.2, 2.3 Hz, 2 H), 7.58 (d,
J = 2.8 Hz, 2 H), 7.54 (m, 3 H), 7.28 (dd, J = 9.2, 2.3 Hz, 2 H).
GC-MS: m/z = 263 (M+).
GC-MS: m/z = 231 (M+).
3-(2-Methoxyhenoxy)benzonitrile (Table 1, entry 17)
Yield: 74%; white solid; mp 49–50 °C.
1H NMR (DMSO-d6): d = 7.52–7.49 (m, 2 H), 7.27–7.23 (m, 3 H),
7.16–7.12 (m, 2 H), 7.02 (m, 1 H), 3.73 (s, 3 H, OCH3).
7-(2-Cyanophenoxy)-4-methylcoumarin (Table 4, entry 1)
Yield: 86%; yellow solid; mp 164–165 °C.
1H NMR (DMSO-d6): d = 7.97 (d, J = 6.8 Hz, 1 H), 7.85 (d, J = 8.7
Hz, 1 H), 7.75 (m, 1 H), 7.42 (m, 1 H), 7.21 (d, J = 8.4 Hz, 1 H),
7.14 (d, J = 2.1 Hz, 1 H), 7.12 (d, J = 2.0 Hz, 1 H), 6.37 (s, 1 H),
2.45 (s, 3 H, CH3).
GC-MS: m/z = 225 (M+).
3-(4-Chlorophenoxy)benzonitrile (Table 1, entry 18)
Yield: 81%; white solid; mp 66–67 °C.
1H NMR (DMSO-d6): d = 7.64–7.58 (m, 2 H), 7.55 (s, 1 H), 7.48 (d,
J = 8.9 Hz, 2 H), 7.38 (t, m, 1 H), 7.12 (d, J = 8.8 Hz, 2 H).
13C NMR (DMSO-d6): d = 160.09, 158.64, 157.59, 154.84, 153.45,
136.03, 134.86, 127.92, 125.60, 119.85, 116.87, 116.05, 115.37,
113.58, 106.85, 104.38, 18.64.
GC-MS: m/z = 229 (M+).
GC-MS: m/z = 277 (M+).
Anal. Calcd for C17H11NO3 (277.28): C, 73.64; H, 4.00; N, 5.05.
Found: C, 73.26; H, 3.96; N, 4.85.
2-[4-(Imidazol-1-yl)]phenoxybenzonitrile (Table 1, entry 19)
Yield: 98%; white solid; mp 126–127 °C.
1H NMR (DMSO-d6): d = 8.26 (s, 1 H), 7.93 (d, J = 7.0 Hz, 1 H),
7.75 (d, J = 8.1 Hz, 3 H), 7.70 (t, J = 7.4 Hz, 1 H), 7.32 (m, 3 H),
7.13 (s, 1 H), 7.04 (d, J = 8.4 Hz, 1 H).
13C NMR (DMSO-d6): d = 159.06, 153.88, 136.12, 135.83, 134.70,
134.33, 130.39, 124.48, 122.89, 121.28, 118.67, 118.12, 116.33,
103.40.
8-(2-Cyanophenoxy)quinoline (Table 4, entry 2)
Yield: 91%; yellow solid; mp 155–156 °C.
1H NMR (DMSO-d6): d = 8.85 (dd, J = 4.0, 1.62 Hz, 1 H), 8.49 (t,
J = 6.8 Hz, 1 H), 7.97 (m, 1 H), 7.88 (d, J = 1.5 Hz, 1 H), 7.70–7.66
(m, 3 H), 7.47 (m, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.56 (d, J = 8.5
Hz, 1 H).
GC-MS: m/z = 261 (M+).
13C NMR (DMSO-d6): d = 160.55, 150.63, 149.28, 140.39, 136.39,
134.87, 133.76, 129.75, 126.86, 126.00, 122.54, 122.27, 120.80,
116.27, 115.72, 101.18.
Anal. Calcd for C16H11N3O (261.29): C, 73.55; H, 4.24; N, 16.08.
Found: C, 73.12; H, 4.20; N 15.76.
GC-MS: m/z = 246 (M+).
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

1312
F. Li et al.
PAPER
Anal. Calcd for C16H10N2O (246.27): C, 78.03; H, 4.09; N, 11.38.
Found: C, 77.85; H, 4.08; N, 11.31.
Anal. Calcd for C17H12N2O (260.30): C, 78.44; H, 4.65; N, 10.76.
Found: C, 78.04; H, 4.34; N, 10.29.
8-(4-Cyanophenoxy)quinoline (Table 4, entry 3)
Yield: 78% yield; yellow solid; mp 113–114 °C.
2-Methyl-4-(4-nitrophenoxy)quinoline (Table 4, entry 8)
Yield: 80%; orange solid; mp 164–165 °C.
1H NMR (DMSO-d6): d = 8.82 (m, 1 H), 8.49 (dd, J = 8.3, 1.2 Hz,
1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 2 H), 7.69 (m, 1
H), 7.63–7.60 (m, 2 H), 6.97 (d, J = 8.7 Hz, 2 H).
13C NMR (DMSO-d6): d = 162.97, 151.09, 149.69, 141.13, 136.93,
134.79, 130.29, 127.45, 126.49, 122.76, 121.71, 119.33, 117.37,
104.63.
1H NMR (DMSO-d6): d = 8.35 (d, J = 9.0 Hz, 2 H), 8.10 (d, J = 7.9
Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.81(t, J = 7.1 Hz, 1 H), 7.8 (t,
J = 7.3 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 2 H), 6.95 (s, 1 H), 2.59 (s, 3
H, CH3).
13C NMR (DMSO-d6): d = 160.85, 160.66, 159.22, 149.62, 144.38,
130.93, 128.85, 126.82, 126.51, 121.61, 120.62, 119.97, 108.83,
25.54.
GC-MS: m/z = 246 (M+).
GC-MS: m/z = 280 (M+).
Anal. Calcd for C16H10N2O (246.27): C, 78.03; H, 4.09; N, 11.38.
Found: C, 77.82; H, 4.10; N, 11.25.
Anal. Calcd for C16H12N2O3 (280.29): C, 68.56; H, 4.32; N, 9.99.
Found: C, 68.16; H, 4.29; N, 9.89.
8-(4-Nitrophenoxy)quinoline (Table 4, entry 4)
Yield: 94%; yellow solid; mp 159–160 °C.
5-(2-Cyanophenoxy)-2-picoline (Table 4, entry 9)
Yield: 74%; yellow oil.
1H NMR (DMSO-d6): d = 8.83 (dd, J = 4.1, 1.6 Hz, 1 H), 8.50 (m,
1 H), 8.19 (dd, J = 7.2, 2.1 Hz, 2 H), 7.99 (d, J = 1.5 Hz, 1 H), 7.72–
7.69 (m, 3 H), 7.021 (dd, J = 7.2, 2.1 Hz, 2 H).
13C NMR (DMSO-d6): d = 164.69, 151.17, 149.60, 142.17, 141.02,
136.96, 130.32, 127.46, 126.74, 126.41, 122.80, 121.88, 116.79.
1H NMR (DMSO-d6): d = 8.37 (d, J = 2.7 Hz, 1 H), 7.91 (dd,
J = 7.7, 1.5 Hz, 1 H), 7.67 (m, 1 H), 7.55 (m, 1 H), 7.37–7.31 (m, 2
H), 6.97 (d, J = 8.5 Hz, 1 H), 2.50 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 159.14, 155.15, 149.88, 141.30, 135.72,
134.66, 128.13, 124.67, 124.33, 117.41, 116.21, 103.16, 23.76.
GC-MS: m/z = 266 (M+).
GC-MS: m/z = 210 (M+).
Anal. Calcd for C15H10N2O3 (266.26): C, 67.67; H, 3.79; N, 10.52.
Found: C, 67.42; H, 3.78; N, 10.48.
Anal. Calcd for C13H10N2O (210.24): C, 74.27; H, 4.79; N, 13.33.
Found: C, 73.91; H, 4.96; N, 13.52.
8-(3-Cyanophenoxy)quinoline (Table 4, entry 5)
Yield: 64%; yellow solid; mp 109–110 °C.
5-(4-Cyanophenoxy)-2-picoline (Table 4, entry 10)
Yield: 78%; incarnadine solid; mp 78–79 °C.
1H NMR (DMSO-d6): d = 8.84 (s, 1 H), 8.47 (d, J = 7.6 Hz, 1 H),
7.93 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.7 Hz, 1 H), 7.61 (m, 1 H),
7.53 (m, 3 H), 7.39 (s, 1 H), 7.19 (d, J = 3.2 Hz, 1 H).
13C NMR (DMSO-d6): d = 159.38, 150.94, 150.43, 141.11, 136.88,
131.61, 130.29, 127.42, 126.54, 125.94, 122.73, 122.13, 120.86,
120.29, 118.77, 112.86.
1H NMR (DMSO-d6): d = 8.34 (d, J = 2.5 Hz, 1 H), 7.85 (d, J = 8.8
Hz, 2 H), 7.53 (dd, J = 8.4, 2.7 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H),
7.12 (d, J = 8.8 Hz, 2 H), 2.50 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 161.46, 155.25, 149.49, 141.92, 135.17,
128.88, 124.77, 119.08, 118.28, 105.90,23.82.
GC-MS: m/z = 246 (M+).
GC-MS: m/z = 210 (M+).
Anal. Calcd for C16H10N2O (246.27): C, 78.03; H, 4.09; N, 11.38.
Found: C, 77.62; H, 4.13; N, 11.16.
Anal. Calcd for C13H10N2O (210.24): C, 74.27; H, 4.79; N, 13.33.
Found: C, 73.91; H, 4.72; N, 13.50.
4-(2-Cyanophenoxy)-2-methylquinoline (Table 4, entry 6)
Yield: 75%; rose pink solid; mp 111–112 °C.
5-(4-Nitrophenoxy)-2-picoline (Table 4, entry 11)
Yield: 70%; yellow solid; mp 66–67 °C.
1H NMR (DMSO-d6): d = 8.21 (d, J = 8.1 Hz, 1 H), 8.05 (d, J = 6.8
Hz, 1 H), 7.98 (d, J = 8.9 Hz, 1 H), 7.82 (m, 2 H), 7.63 (d, J = 7.5
Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 6.73 (s,
1 H), 2.57 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 161.17, 160.46, 156.96, 150.09, 136.84,
135.61, 131.57, 129.37, 127.25, 127.09, 122.28, 122.16, 120.13,
116.38, 107.25, 106.06, 26.22.
1H NMR (DMSO-d6): d = 8.38 (d, J = 2.6 Hz, 1 H), 8.25 (d, J = 9.2
Hz, 2 H), 7.58 (dd, J = 8.5, 2.7 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 1 H),
7.16 (d, J = 9.2 Hz, 2 H), 2.51 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 163.80, 156.21, 150.04, 143.60, 142.71,
129.77, 127.32, 125.50, 118.33, 24.49.
GC-MS: m/z = 230 (M+).
Anal. Calcd for C12H10N2O3 (230.23): C, 62.60; H, 4.38; N, 12.17.
Found: C, 62.27; H, 4.42; N, 12.46.
GC-MS: m/z = 260 (M+).
Anal. Calcd for C17H12N2O (260.30): C, 78.44; H, 4.65; N, 10.76.
Found: C, 78.01; H, 4.60; N, 10.83.
5-(3-Cyanophenoxy)-2-picoline (Table 4, entry 12)
Yield: 67% yield; white solid; mp 63–64 °C.
4-(4-Cyanophenoxy)-2-methylquinoline (Table 4, entry 7)
Yield: 62% yield; rose pink solid; mp 182–183 °C.
1H NMR (DMSO-d6): d = 8.30 (d, J = 2.3 Hz, 1 H), 7.62–7.57 (m,
2 H), 7.53 (s, 1 H), 7.47–7.45 (m, 1 H), 7.36–7.32 (m, 2 H), 2.48 (s,
3 H, CH3).
13C NMR (DMSO-d6): d = 158.39, 155.20, 151.03, 141.90, 132.64,
128.59, 128.42, 125.29, 123.97, 122.25, 119.18, 113.91, 24.41.
1H NMR (DMSO-d6): d = 8.11 (d, J = 7.6 Hz, 1 H), 7.97 (d, J = 7.1
Hz, 3 H), 7.79 (s, 1 H), 7.58 (s, 1 H), 7.43 (d, J = 7.2 Hz, 2 H), 6.84
(s, 1 H), 2.58 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 161.22, 160.13, 159.68, 150.19, 136.10,
131.49, 129.42, 127.01, 122.28, 121.88, 120.57, 119.55, 108.71,
108.65, 26.19.
GC-MS: m/z = 210 (M+).
Anal. Calcd for C13H10N2O (210.24): C, 74.27; H, 4.79; N, 13.33.
Found: C, 74.24; H, 4.82; N, 13.74.
GC-MS: m/z = 260 (M+).
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York

PAPER
Synthesis of Diaryl Ethers/Sulfides and Heteroaryl Ethers/Sulfides
1313
2-(2-Cyanophenylthio)pyrimidine (Table 5, entry 1)
Yield: 87% yield; incarnadine solid; mp 111–112 °C.
1H NMR (DMSO-d6): d = 8.64 (d, J = 4.5 Hz, 2 H), 8.04 (d, J = 7.3
Hz, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.81 (t, J = 7.3 Hz, 1 H), 7.72–
7.69 (m, 1 H), 7.31 (d, J = 4.4 Hz, 1 H).
13C NMR (DMSO-d6): d = 170.59, 159.48, 137.99, 135.42, 135.12,
133.19, 131.66, 119.776, 119.60, 118.30.
GC-MS: m/z = 214 (M+).
A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(g) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F.
J. Am. Chem. Soc. 1999, 121, 3224. (h) Theil, F. Angew.
Chem. Int. Ed. 1999, 38, 2345.
(5) For a recent review on copper-mediated aromatic C–O, C–
N, and C–S bond formation see: Ley, S. V.; Thomas, A. W.
Angew. Chem. Int. Ed. 2003, 42, 5400.
(6) Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W.
J. III. J. Org. Chem. 1998, 63, 6338.
Anal. Calcd for C11H7N3S (213.26): C, 61.95; H, 3.31; N, 19.70.
Found: C, 61.51; H, 3.31; N, 20.02.
(7) See for examples: (a) Khalafi-Nezhad, A.; Rad, M. N. S.;
Khoshnood, A. Synthesis 2004, 583. (b) Hazarkhani, H.;
Karimi, B. Synthesis 2004, 1239. (c) Wannberg, J.; Larhed,
M. J. Org. Chem. 2003, 68, 5750. (d) Martin, B.; Sekljic,
H.; Chassaing, C. Org. Lett. 2003, 5, 1851. (e) Bose, A. K.;
Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.; Banik, B. K.
Synthesis 2002, 1578. (f) Sarju, J.; Danks, T. N.; Wagnera,
G. Tetrahedron Lett. 2004, 45, 7675. (g) Chaouchi, M.;
Loupy, A.; Marque, S.; Petit, A. Eur. J. Org. Chem. 2002,
1278.
(8) For some recent reviews on this topic see: (a) Santagada,
V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem. 2002, 9,
1251. (b) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem.
Res. 2002, 35, 717. (c) Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199. (d) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225. (e) Deshayes, S.;
Liagre, M.; Loupy, A.; Luche, J. L.; Petit, A. Tetrahedron
1999, 55, 10851.
(9) Li, F.; Wang, Q.; Ding, Z.; Tao, F. Org. Lett. 2003, 5, 2169.
(10) For reports on the use of microwave irradiation in the
synthesis of diaryl ethers see: (a) He, H.; Wu, Y. J.
Tetrahedron Lett. 2003, 44, 3445. (b) Fan, L.; Zhang, Y.;
Wang, Y.; Liu, J.; Ma, M.; Chen, S. Chem. Res. Appl. 2001,
13, 336. (c) Narsaiah, A. V.; Nagaiah, K. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 2004, 43, 2478.
(d) Lee, J. C.; Choi, J. H.; Lee, J. S. Bull. Korean Chem. Soc.
2004, 25, 1117.
(11) Driscoll, P. R. U. S. Patent 349569, 1970.
(12) Hwang, K. J.; Park, S. K. Synth. Commun. 1990, 20, 949.
(13) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron
1992, 48, 3633.
2-(4-Cyanophenylthio)pyrimidine (Table 5, entry 2)
Yield: 80% yield; incarnadine solid; mp 114–115 °C.
1H NMR (DMSO-d6): d = 8.6 (d, J = 4.8 Hz, 2 H), 7.92 (d, J = 8.2
Hz, 2 H), 7.83 (d, J = 8.2 Hz, 2 H), 7.31 (t, J = 4.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 170.03, 158.79, 136.31, 135.31, 133.26,
119.06, 118.82, 111.99.
GC-MS: m/z = 214 (M+).
Anal. Calcd for C11H7N3S (213.26): C, 61.95; H, 3.31; N, 19.70.
Found: C, 61.52; H, 3.22; N, 19.43.
2-(4-Nitrophenylthio)pyrimidine (Table 5, entry 3)
Yield: 78% yield; yellow solid; mp 114–115 °C.
1H NMR (DMSO-d6): d = 8.66 (d, J = 4.8 Hz, 2 H), 8.28 (d, J = 8.7
Hz, 2 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.34 (t, J = 4.8 Hz, 1H).
13C NMR (DMSO-d6): d = 169.80, 158.88, 147.96, 138.57, 135.40,
124.44, 119.25.
GC-MS: m/z = 233 (M+).
Anal. Calcd for C10H7N3O2S (233.25): C, 51.49; H, 3.02; N, 18.02.
Found: C, 51.52; H, 3.08; N, 18.50.
Acknowledgment
We gratefully acknowledge financial support for this project from
the National Natural Science Foundation of China through grant
20372015 and the young teacher fellowship from this university (F.
Li).
(14) Wang, J. X.; Zhang, M. L.; Hu, Y. L. Synth. Commun. 1998,
28, 2407.
(15) Kumar, S.; Kapoor, M.; Surolia, N.; Surolia, A. Synth.
Commun. 2004, 34, 413.
(16) Tan d = 0.825, see: Gabriel, C.; Gabriel, S.; Grant, E. H.;
Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
27, 213.
(17) (a) Kuhnert, N. Angew. Chem. Int. Ed. 2002, 41, 1863.
(b) Sudrik, S. G.; Chavan, S. P.; Chandrakumar, K. R. S.;
Pal, S.; Date, S. K.; Chavan, S. P.; Sonawane, H. R. J. Org.
Chem. 2002, 67, 1574.
(18) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005.
(19) Under the usual refluxing acetonitrile conditions the same
reaction catalyzed by potassium fluoride-alumina and 18-
crown-6 occurred in 83% yield in 120 hours.6
References
(1) See for example: (a) Nicolaou, K. C.; Boddy, C. N. C. J. Am.
Chem. Soc. 2002, 124, 10451. (b) Evans, D. A.; Dinsmore,
C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.; Trotter,
B. W.; Katz, J. L. Angew. Chem. Int. Ed. 1998, 37, 2704.
(c) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan,
S.; Koumbis, A. E.; Bando, T.; Ramanjulu, J. M. Angew.
Chem. Int. Ed. 1998, 37, 2717.
(2) For a review of the Ullmann ether synthesis see: Moroz, A.
A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974, 43, 679.
(3) For a recent review see: Sawyer, J. S. Tetrahedron 2000, 56,
5045.
(4) (a) Gao, G. Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. Org.
Lett. 2003, 5, 3261. (b) Ma, D.; Cai, Q. Org. Lett. 2003, 5,
3799. (c) Xu, L. W.; Xia, C. G.; Li, J. W.; Hu, X. X. Synlett
2003, 2071. (d) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer,
P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(e) Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N.
A.; Olah, G. A. J. Org. Chem. 2001, 66, 633. (f) Aranyos,
(20) (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org.
Lett. 2002, 4, 2803. (b) Van Bierbeek, A.; Gingras, M.
Tetrahedron Lett. 1998, 39, 6283. (c) Lindley, J.
Tetrahedron 1984, 40, 1433.
(21) Baghurst, D. R.; Mingos, D. M. P. J. Organomet. Chem.
1990, 384, C57.
Synthesis 2005, No. 8, 1305–1313 © Thieme Stuttgart · New York