Microwave-assisted construction of diaryl ethers directly from arylmethanesulfonates as convenient latent phenols with aryl halides

Article abstract of DOI:10.1080/00397910701412901

The microwave-assisted synthesis of diaryl ethers directly from aryl halides and arylmethanesulfonates, which as latent phenols obviate a deprotection step prior to the SNAr reaction, in the presence of Cs2CO3 is described. The reaction time was very short (6-9-min), and good to excellent yields (53-90%) with the wide substrate scope were achieved without any catalyst. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701412901

Synthetic Communicationsw, 37: 2411–2420, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701412901
Microwave-Assisted Construction of Diaryl
Ethers Directly from Arylmethanesulfonates
as Convenient Latent Phenols with Aryl
Halides
Hui Xu and Yang Chen
College of Science, Northwest A&F University, Yangling, Shaanxi
Province, China
Abstract: The microwave-assisted synthesis of diaryl ethers directly from aryl halides
and arylmethanesulfonates, which as latent phenols obviate a deprotection step prior to
the SNAr reaction, in the presence of Cs2CO3 is described. The reaction time was very
short (6–9 min), and good to excellent yields (53–90%) with the wide substrate scope
were achieved without any catalyst.
Keywords: aryl halides, arylmethanesulfonates, diaryl ethers, microwave, SNAr
reaction
Diaryl ether units are known to be in a variety of natural and biological
products such as vancomycin and riccardin.[1] Because the classical reaction
of Ullmann ether synthesis often requires exceedingly strenuous conditions
and generally gives lower yields, a number of interesting methods for the con-
struction of diaryl ethers have been developed in recent years.[2–6] We all
know that the methanesulfony group is a useful and potent protecting group
for a phenol because of its robust behavior under a wide variety of reaction
conditions,[7,8] so it is very interesting that the methanesulfonyl protecting
group for a phenol is unmasked under the conditions of the SNAr reaction
with an aryl halide, producing diaryl ether directly. That is, the deprotection
step is obviated. Although Dinsmore reported the synthesis of diaryl ethers
Received October 16, 2006
Address correspondence to Hui Xu, College of Science, Northwest A&F Univer-
sity, Yangling 712100, Shaanxi Province, China. E-mail: xhzjyy@yahoo.com.cn
2411

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H. Xu and Y. Chen
from arylmethanesulfonates and 2-fluoronitrobenzene, this method required
very long reaction times (6–48 h) and had a narrow application scope of
substrates.[7]
Microwave-assisted organic synthesis has attracted considerable attention
in the past decade.[9,10] Microwave irradiation often leads to a remarkable
decrease in reaction time, increased yields, and easier workup consistent
with green chemistry protocols.[11] To the best of our knowledge, however,
the direct catalyst-free synthesis of diaryl ethers from aryl methanesulfonates
(as latent phenols) and aryl halides using high-speed microwave techniques
has not been reported. Herein we describe our studies on the microwave-
assisted C-O bond SNAr coupling of aryl halides and various aryl methanesul-
fonates without any catalyst (Scheme 1).
From the results shown in Table 1, it can be seen that a range of aryl
methanesulfonates including those that have electron-deficient and electron-
rich groups were effective for this C-O cross-coupling SNAr reaction with
electron-deficient aryl halides (X ¼ F, Cl, Br), such as 2-fluoronitrobenzene,
4-fluoronitrobenzene, 2-fluorobenzonitrile, 2-chloronitrobenzene, and 4-bro-
monitrobenzene, in the presence of 2 equivalents of cesium carbonate as the
base under microwave irradiation in DMSO medium. Good to excellent
yields (53–90%) were obtained in 6–9 min.
For example, 2-fluoronitrobenzene (1 mmol) was effectively coupled with
phenyl methanesulfonate (1.5 mmol) to provide the expected 2-(phenoxy)-
nitrobenzene (185.2 mg, 84%) in the presence of Cs2CO3 (2 mmol) and
dimethyl sulfoxide (DMSO) (10 mL) under microwave irradiation at 230 W
for 8 min (entry 1), but it took 40 h to complete this reaction in DMSO under
the usual heating conditions.[7]
Moreover, it should be recalled that aryl methanesulfonates with electron-
deficient groups behave poorly or are completely inert toward diaryl ether
formation. However, it is noteworthy in our reaction that the electron-poor
aryl methanesulfonates (entries 2–4, 8–10, 14, 16, 17, 19, 20) could
smoothly be coupled with the activated aryl halides (X ¼ F, Cl, Br) within
8 min to give good to excellent yields. Especially for entries 2 and 8, the
reactions with extremely electron-poor 4-nitrophenyl methanesulfonate
afforded 2-(40-nitrophenoxy)nitrobenzene (70%) and 4,40-dinitrodiphenyl
ether (78%) respectively.
Scheme 1.

Table 1. Microwave-assisted synthesis of diaryl ethers
Entry
1
Aryl halides
Arylmethanesulfonates
Diaryl ethers
Time (min)
8
Yield (%)
84
2
3
8
8
70
90
4
5
6
7
8
8
9
8
8
8
90
69
68
77
78
(continued)

Table 1. Continued
Entry
9
Aryl halides
Arylmethanesulfonates
Diaryl ethers
Time (min)
8
Yield (%)
82
10
11
12
8
9
8
77
74
69
13
14
8
6
55
90

Microwave-Assisted Synthesis of Diaryl Ethers
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H. Xu and Y. Chen
Meanwhile, we investigated the reaction activity of the aryl halides
(X ¼ F, Cl, Br) and found that the sequence was F . Cl ꢀ Br (entries 3, 4,
16, 17, 19, 20). In some cases, the steric effect of the substituted group
on the aryl methanesulfonates was clear, such as para-tert-butylphenyl
methanesulfonate (entry 6, 68%, and entry 13, 55%) and para-chlorophenyl
methanesulfonate (entry 4, 90%, and entry 14, 90%).
In conclusion, we have introduced a useful, mild, and efficient C-O bond
cross-coupling SNAr reaction for the facile preparation of diaryl ethers directly
from aryl methanesulfonates (as latent phenols) without the deprotection step
and aryl halides (X ¼ F, Cl, Br) in the presence of Cs2CO3 under microwave
irradiation. The reaction time was very short (6–9 min) and good to excellent
yields (53–90%) with the wide substrate scope were achieved without any
catalyst. Meanwhile, we hope this efficient method could render the methane-
sulfonate a useful, previously underutilized protecting group for phenols. Fur-
thermore, efforts to expand the scope of this method in the construction of
biologically important diaryl ethers are ongoing in our laboratory.
The materials were used as purchased, and DMSO was used directly without
any additional purification. Melting points were uncorrected. 1H NMR spectra
were recorded on a Bruker Avance DMX 400- or 200-MHz instrument using
TMS as internal standard and CDCl3 as solvent. High resolution mass
spectrometry (HRMS) and electron ionization mass spectrometry (EIMS)
were carried out with an Apex II Bruker 4.7T AS and a Thermo DSQ gas
chromatography mass spectrometry (GC/MS) instrument respectively.
Elemental analysis was executed on Carlo-Ebbra 1106 CHN microanalyzer.
Microwave irradiation was performed in a Haier microwave oven, MO-2270M1.
MICROWAVE-ASSISTED SYNTHESIS OF DIARYL ETHERS:
GENERAL PROCEDURE
Aryl halide (X ¼ F, Cl, Br, 1 mmol), the aryl methanesulfonate (1.5 mmol)
and Cs2CO3 (2 mmol) were added to 10 mL of DMSO. The reaction was
found to be insensitive to air and moisture, hence DMSO was used directly
without any additional purification and there was no need for an inert atmos-
phere. The mixture was reacted in a Haier microwave oven (model MO-
2270M1) at 230 W for 6–9 min, monitored by thin-layer chromatography
(TLC). After completion of the reaction, it was cooled to room temperature,
poured into 30 mL of ice water, and stirred for 5 min. Then 60 mL of
EtOAc were added to the mixture, the organic layer was separated, and the
aqueous layer was extracted by EtOAc (2 ꢁ 60 mL). The combined organic
extracts were washed with 40 mL of brine and dried over anhydrous
MgSO4. After removal of the solvent under reduced pressure, the residue
was purified by preparative thin-layer chromatography (PTLC) to give the
1
pure diaryl ether. All compounds were characterized by H NMR (200 or
400 MHz), HRMS, or elemental analysis, EI-MS, and melting point.

Microwave-Assisted Synthesis of Diaryl Ethers
DATA
2417
2-(Phenoxy)nitrobenzene (1) and (18)
1
Yellow liquid; H NMR (200 MHz, CDCl3): d ¼ 6.83 (5H, m), d 7.32 (3H,
m), d 7.90 (1H, dd, J ¼ 8.2 Hz, J ¼ 1.6 Hz); GC/MS (EI, 70eV): m/z
(%) ¼ 216 (M þ Hþ, 100), 186 (78), 170 (35). Anal. calcd. for C12H9NO3:
C, 66.97; H, 4.18; N, 6.51. Found: C, 66.69; H, 4.45; N, 6.38.
2-(40-Nitrophenoxy)nitrobenzene (2)
1
Yellow solid, mp 101.1–101.98C; H NMR (400 MHz, CDCl3): d ¼ 7.03
(2H, m), 7.23 (1H, dd, J ¼ 8.4 Hz, J ¼ 1.2 Hz), 7.41 (1H, dt, J ¼ 8.0 Hz,
J ¼ 1.6 Hz), 7.67 (1H, dt, J ¼ 8.0 Hz, J ¼ 1.2 Hz), 8.06 (1H, dd,
J ¼ 8.0 Hz, J ¼ 1.6 Hz); 8.22 (2H, m); GC/MS (EI, 70 eV): m/z
(%) ¼ 260 (Mþ, 9.9), 139 (53.8), 122 (100). Anal. calcd. for C12H8N2O5:
C, 55.39; H, 3.10; N, 10.77. Found: C, 55.27; H, 3.26; N, 10.71.
2-(20-Chlorophenoxy)nitrobenzene (3) and (17)
Pale yellow liquid; 1H NMR (400 MHz, CDCl3): d ¼ 6.83 (1H, dd,
J ¼ 8.4 Hz, J ¼ 1.2 Hz), 7.07 (1H, dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz), 7.16 (3H,
m), 7.47 (2H, m), 7.97 (1H, dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz); HRMS-FAB: m/z
[M þ NH4]þ calcd. for C12H8NO3Cl: 267.0531; found: 267.0535.
2-(40-Chlorophenoxy)nitrobenzene (4) and (16)
Pale yellow liquid; 1H NMR (400 MHz, CDCl3): d ¼ 6.96 (3H, m), 7.21 (1H,
t, J ¼ 8.0 Hz), 7.31 (2H, m), 7.51 (1H, dt, J ¼ 8.4 Hz, J ¼ 1.6 Hz), 7.95 (1H,
dd, J ¼ 8.4 Hz, J ¼ 1.6 Hz); GC/MS (EI, 70eV): m/z (%) ¼ 251 (Mþ, 10.8),
249 (Mþ, 32.5), 122 (100). Anal. calcd. for C12H8NO3Cl: C, 57.73; H, 3.23; N,
5.61. Found: C, 57.62; H, 3.29; N, 5.54.
2-(3-Methylphenoxy)nitrobenzene (5) and (15)
Pale yellow liquid; 1H NMR (400 MHz, CDCl3): d ¼ 2.34 (3H, s), 6.83 (2H,
m), 6.99 (2H, m), 7.15 (1H, t, J ¼ 7.6 Hz), 7.23 (1H, t, J ¼ 8.0 Hz), 7.46 (1H,
dt, J ¼ 8.0 Hz, J ¼ 1.6 Hz), 7.93 (1H, dd, J ¼ 7.6 Hz, J ¼ 1.6 Hz); HRMS-
FAB: m/z [M þ NH4]þ calcd. for C13H11NO3: 247.1077; found: 247.1080.

2418
H. Xu and Y. Chen
2-(4-tert-Butylphenoxy)nitrobenzene (6)
1
Yellow liquid; H NMR (400 MHz, CDCl3): d ¼ 1.32 (9H, s), 6.97 (2H, d,
J ¼ 8.8 Hz), 6.99 (1H, d, J ¼ 8.0 Hz), 7.14 (1H, t, J ¼ 7.6 Hz), 7.37 (2H, d,
J ¼ 8.8 Hz), 7.45 (1H, m), 7.92 (1H, d, J ¼ 8.0 Hz); HRMS-FAB: m/z
[M þ NH4]þ calcd. for C16H17NO3: 289.1547; found: 289.1552.
4-(Phenoxy)nitrobenzene (7)
White solid, mp 55.9–56.38C; 1H NMR (400 MHz, CDCl3): d ¼ 6.99 (2H, d,
J ¼ 12 Hz), d 7.08 (2H, d, J ¼ 8.4 Hz), d 7.24 (1H, t, J ¼ 6.8 Hz), d 7.41 (2H,
t, J ¼ 8.4 Hz), d 8.18 (2H, d, J ¼ 12 Hz); GC/MS (EI, 70eV): m/z (%) ¼ 215
(Mþ, 100), 185 (24.9), 77 (62.2). Anal. calcd. for C12H9NO3: C, 66.97; H,
4.18; N, 6.51. Found: C, 66.75; H, 4.36; N, 6.58.
4-(40-Nitrophenoxy)nitrobenzene (8)
Pale yellow solid, mp 144.5–144.98C; 1H NMR (400 MHz, CDCl3): d ¼ 7.15
(4H, m), 8.28 (4H, m); MS (EI, 70eV): GC/m/z (%) ¼ 260 (Mþ, 100), 230
(40), 139 (65.1). Anal. calcd. for C12H8N2O5: C, 55.39; H, 3.10; N, 10.77.
Found: C, 55.21; H, 3.36; N, 10.66.
4-(20-Chlorophenoxy)nitrobenzene (9) and (19)
1
White solid, mp 76.8–77.08C; H NMR (400 MHz, CDCl3): d ¼ 6.93 (2H,
m), d 7.16 (1H, dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz), d 7.23 (1H, dt, J ¼ 8.0 Hz,
J ¼ 1.6 Hz), d 7.33 (1H, dt, J ¼ 8.0 Hz, J ¼ 1.6 Hz), d 7.51 (1H, dd,
J ¼ 8.0 Hz, J ¼ 1.6 Hz), d 8.19 (2H, m); HRMS-FAB: m/z [M þ NH4]þ
calcd. for C12H8NO3Cl: 267.0531; found: 267.0529.
4-(40-Chlorophenoxy)nitrobenzene (10) and (20)
1
White solid, mp 75.8–76.18C; H NMR (400 MHz, CDCl3): d ¼ 7.00 (4H,
m), d 7.38 (2H, dd, J ¼ 6.8 Hz, J ¼ 2.4 Hz), d 8.20 (2H, d, J ¼ 7.2 Hz,
J ¼ 2.4 Hz); HRMS-FAB: m/z [M þ NH4]þ calcd. for C12H8NO3Cl:
267.0531; found: 267.0532.

Microwave-Assisted Synthesis of Diaryl Ethers
4-(3-Methylphenoxy)nitrobenzene (11)
2419
White solid, mp 61.9–62.28C; 1H NMR (400 MHz, CDCl3): d ¼ 2.78 (3H, s),
d 6.88 (2H, m), d 6.99 (2H, d, J ¼ 9.2 Hz), d 7.05 (1H, d, J ¼ 8.0 Hz), d 7.29
(1H, t, J ¼ 8.0 Hz), d 8.18 (2H, d, J ¼ 9.2 Hz); HRMS-FAB: m/z
[M þ NH4]þ calcd. for C13H11NO3: 230.0812; found: 230.0811.
4-(4-tert-Butylphenoxy)nitrobenzene (12)
White solid, mp 61.2–61.68C; 1H NMR (400 MHz, CDCl3): d ¼ 1.35 (9H, s),
d 6.99 (4H, m), d 7.41 (2H, m), d 8.18 (2H, d, J ¼ 8.8 Hz); HRMS-FAB: m/z
[M þ NH4]þ calcd. for C16H17NO3: 289.1547; found: 289.1546.
2-(4-tert-Butylphenoxy)benzonitrile (13)
1
White liquid; H NMR (400 MHz, CDCl3): d ¼ 1.33 (9H, s), d 6.84 (1H, d,
J ¼ 8.8 Hz), d 7.00 (2H, m), d 7.08 (1H, t, J ¼ 7.2 Hz), d 7.39 (3H, m),
d 7.63 (1H, dd, J ¼ 7.6 Hz, J ¼ 1.6 Hz); HRMS-FAB: m/z [M þ NH4]þ
calcd. for C17H17NO: 269.1648; found: 269.1648.
2-(4-Chlorophenoxy)benzonitrile (14)
White solid, mp 85.0–85.78C; 1H NMR (400 MHz, CDCl3): d ¼ 6.85 (1H, d,
J ¼ 8.8 Hz), d 7.01 (2H, m), d 7.14 (1H, t, J ¼ 7.2 Hz), d 7.35 (2H, m), d 7.47
(1H, m), d 7.66 (1H, dd, J ¼ 8.0 Hz, J ¼ 2.0 Hz); HRMS-FAB: m/z
[M þ NH4]þ calcd. for C13H8NOCl: 247.0627; found: 247.0633.
ACKNOWLEDGMENT
This study was supported by the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry (No.
14110101). We also thank Northwest A&F University for the financial
support from the Program for Excellent Talents.
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