C(aryl)-O bond formation from aryl methanesulfonates via consecutive deprotection and SNAr reactions with aryl halides in an ionic liquid

Article abstract of DOI:10.3390/12040861

An efficient K₃PO₄-mediated synthesis of unsymmetrical diaryl ethers using the ionic liquid [Bmim]BF₄ (1-butyl-3-methylimidazolium tetrafluoroborate) as solvent has been developed. The procedure involves consecutive deprotection of aryl methanesulfonates and a nucleophilic aromatic substitution (S_NAr) with activated aryl halides.

Full text of DOI:10.3390/12040861

Molecules 2007, 12, 861-867
molecules
ISSN 1420-3049
2007 by MDPI
www.mdpi.org/molecules
©
Communication
C(aryl)-O Bond Formation from Aryl Methanesulfonates via
Consecutive Deprotection and S Ar Reactions with Aryl Halides
N
in an Ionic Liquid
†
Hui Xu * and Yang Chen
†
College of Science, Northwest A&F University, Yangling 712100, P.R. China; E-mail:
chenyanggzky@nwsuaf.edu.cn
*
Author to whom correspondence should be addressed; E-mail: orgxuhui@nwsuaf.edu.cn
Received: 28 March 2007; in revised form: 19 April 2007 / Accepted: 20 April 2007 / Published: 30
April 2007
Abstract: An efficient K
ionic liquid [Bmim]BF
been developed. The procedure involves consecutive deprotection of aryl methane-
sulfonates and a nucleophilic aromatic substitution (S Ar) with activated aryl halides.
3
4
PO -mediated synthesis of unsymmetrical diaryl ethers using the
4
(1-butyl-3-methylimidazolium tetrafluoroborate) as solvent has
N
Keywords: C(aryl)-O bond, aryl methanesulfonates, nucleophilic aromatic substitution,
diaryl ethers, ionic liquid.
Introduction
In recent years, in the search for green alternatives for traditional organic solvents in chemistry,
ionic liquids have generated considerable interest as environmentally benign reaction media, due to
their unique properties such as ease of recyclability, ability to dissolve a variety of organic, inorganic
and metal complex materials, non-volatile and non-flammable nature and high thermal stability [1]. A
growing number of chemical reactions in these media, such as Kabachnik-Fields reaction [2],
polymerizations [3], hydrogenations [4], Diels-Alder reactions [5], Michael reactions [6], C-P cross-
coupling reactions [7], and Beckmann rearrangements [8], have been reported. Diaryl ethers are very
important intermediates in organic synthesis and are known to be present in a variety of natural

Molecules 2007, 12
862
compounds of biological interest, such as vancomycin and riccardin [9]. The classical Ullmann
reaction for diaryl ether synthesis often requires extremely harsh reaction conditions, i.e. high
o
temperatures (200-300 C), strong polar and toxic solvents and the use of stoichiometric quantities of
copper, and generally gives low yields [10], so a number of other methodologies for the synthesis of
diaryl ethers have been developed in recent years [11]. Meanwhile, the fact that the strategic use of
protective groups is a necessary and time-consuming tactic in organic synthesis is well-known, so a
merging of protective group chemistry with other transformations that can shorten a reaction sequence
and improve synthetic efficiency and convenience is always of great interest. The methanesulfonyl
group, as a useful protective group for phenols due to its robust behavior, has been widely used in a
variety of reactions [12-13]. On the other hand, aryl methanesulfonates have been used as latent
phenols in the nucleophilic aromatic substitution (S Ar) reaction to prepare diaryl ethers [12], but
N
2 3
unfortunately, the reported method requires the use of an excess of expensive Cs CO and toxic
organic solvents, and is applicable to a only a narrow range of substrates [12], therefore the
development of a simpler, greener, cheaper and more efficient route for the synthesis of unsymmetrical
diaryl ethers directly from aryl methanesulfonates and aryl halides that would be useful for a wide
range of substrates is highly desirable. As part of our program directed at developing efficient and new
methodologies for constructing bioactive molecules [14], herein we report a simple and
environmentally benign synthesis of unsymmetrical diaryl ethers via a tandem deprotection of aryl
methanesulfonates/S Ar reaction with activated aryl halides using the ionic liquid [Bmim]BF (1-
N
4
butyl-3-methylimidazolium tetrafluoroborate ) as a solvent (Scheme 1).
Scheme 1. The route of synthesis of unsymmetrical diaryl ethers.
X
R2
OMs
O
O
K PO / heat
3
3
4
R1
R2
R1
R1
[
Bmim]BF4
SNAr
4
1
Deprotection
32-89%
2
1
2
R =H, NO , Cl, CH , Bu-t; R =NO , CN; X=F, Cl, Br
2
3
2
Results and Discussion
As shown in Scheme 1, the C-O bond cross-coupling of phenoxides 2, generated in situ from aryl
methanesulfonates 1, with aryl halides 3 to produce diaryl ethers 4 can be effected in the ionic liquid
4 3 4
[Bmim]BF in the presence of anhydrous K PO . The results for different unsymmetric diaryl ethers
are summarized in Table 1. A wide range of aryl methanesulfonates, including those having electron-
1
deficient and electron-rich groups (R =H, NO
2
, Cl, CH
3
2
, t-Bu) were effective for this C-O cross-
coupling S
N
Ar reaction with activated aromatic halides (R = NO
2
, CN; X=F, Cl, Br) and moderate to
good yields (32-89 %) were obtained.
Moreover, it should be recalled that aryl methanesulfonates with electron-withdrawing groups
typically behave poorly or are completely inert toward diaryl ether formation, but in our reactions such
electron-poor aryl methanesulfonates reacted smoothly with the corresponding aryl halides (X=F, Cl,
Br), mediated by anhydrous K PO , to give the expected products (compounds 4a, 4c, 4e, 4g, 4i, 4l).
3
4

Molecules 2007, 12
863
Particularly good yields were obtained for compounds 4g, 4i and 4c (85 %, 89 % and 88 %,
respectively). When 4-fluoronitrobenzene was reacted with the extremely electron-poor 4’-nitrophenyl
methanesulfonate, 4-(4’-nitrophenoxy)nitrobenzene (4e) was obtained in 42% yield after being stirred
o
in the presence of anhydrous K PO at 110 C for 24.5 h. When 2’-chlorophenyl methanesulfonate was
3
4
reacted with 4-fluoronitro- or 4-bromonitrobenzene and 2-fluoronitro- or 2-chloronitrobenzene, the
corresponding compounds 4-(2’-chlorophenoxy)nitrobenzene (4c) and 2-(2’-chlorophenoxy)nitroben-
zene (4i) were obtained in 72 %/88 % and 89 %/66 % yields, respectively. These results showed that
fluoro derivatives may be replaced by the corresponding bromo or chloro derivatives without causing a
significant decrease in the yields.
a
Table 1. Synthesis of diaryl ethers in [Bmim]BF4
OMs
X
O
K PO / heat
R1
R2
3
4
R1
+
R2
[
Bmim]BF4
4
1
3
1
2
o
b
c
R
4
R
X
Temp. ( C)
100
Time (h)
11
Product
4a
Yield (%)
’-Cl
’-CH
’-Cl
NO
NO
2
4-F
4-F
4-F
4-F
4-F
4-F
2-F
2-F
2-F
2-F
2-F
2-F
70
50
72
52
42
64
85
32
89
55
63
57
66
88
3
3
2
100
20
4b
4c
2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CN
100
7
4
’-t-Bu
’-NO2
H
114
24
4d
4e
4
110
24.5
24.5
12
110
4f
4
’-Cl
’-t-Bu
’-Cl
’-CH3
’-t-Bu
100
4g
4
100
20
4h
4i
2
105
11
3
100
20
4j
4
110
25
4k
4l
4
’-Cl
’-Cl
’-Cl
CN
110
24
2
2
NO2
NO2
2-Cl
4-Br
110
29
4i
110
25
4c
a
All reactions were carried out with 1 (1.5 mmol), 3 (1.0 mmol) and K
3
4
PO (2 mmol) in
b
c
[
Bmim]BF (3 mL) at the appropriate temperature; Reaction temperature; Isolated yield.
4
Next, we also investigated the reusability and the recycling of the ionic liquid [Bmim]BF , and
4
found that it could be easily recovered after the completion of the reaction and reused in the
subsequent reactions without any noticeable loss of efficiency. For this purpose the reaction of 2-
fluoronitro-benzene with 2’-chlorophenyl methanesulfonate mediated by anhydrous K
3 4
PO in
o
[
Bmim]BF was investigated as a model reaction. When the reaction was complete after 11 h at 105 C,
4
as checked by TLC, the reaction mixture was extracted three times with ethyl ether, then the ionic
liquid left in the reaction vessel was dissolved with acetone, filtered and washed by acetone to remove
the solid, and finally the combined acetone extract was evaporated under reduced pressure to give the
recycled ionic liquid, which was reused as the reaction solvent for the next reaction. The ionic liquid
activity did not show any significant decrease after 3 runs and the yields were 88%, 89%, and 89% for
runs 1-3, respectively.

Molecules 2007, 12
864
Conclusions
In summary, we have developed an efficient procedure for the synthesis of unsymmetrical diaryl
ethers via a tandem deprotection of aryl methanesulfonates and S Ar reactions with activated aryl
N
3 4 4
halides mediated by anhydrous K PO and using the ionic liquid [Bmim]BF as solvent. The
advantages of this method are as follows: 1) moderate to good yields are obtained using a wide range
of substrates; 2) a deprotection step is obviated; 3) separation of the products from the ionic liquid
during work-up is very easy; 4) the ionic liquid can be recycled without loss of efficiency, making the
procedure quite simple, convenient and environmentally benign.
Experimental
General
All the solvents were of analytical grade and the reagents were used as purchased. Thin-layer
chromatography (TLC) and preparative thin-layer chromatography (PTLC) were performed with silica
gel plates using silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were
1
determined on a digital melting-point apparatus and were uncorrected. H-NMR spectra were recorded
3
on a Bruker Avance DMX 400 MHz instrument using TMS as internal standard and CDCl as solvent.
HRMS and EIMS were carried out with APEX II Bruker 4.7T AS and Thermo DSQ GC/MS
instrument respectively. Elemental analysis was executed on Carlo-Erba 1106 CHN microanalyzer.
General procedure for the preparation of unsymmetrical diaryl ethers 4
The aryl halide (3, X=F, Cl, Br, 1 mmol), the aryl methanesulfonate (1, 1.5 mmol) and anhydrous
3 4 4
K PO (2 mmol) were added to [Bmim]BF (3 mL). The reaction mixture was stirred for a given time
at the appropriate temperature and monitored by thin-layer chromatography (TLC). After completion
of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl ether (3
x 40 mL). Then the extracts were combined and evaporated under reduced pressure to give a residue
which was purified by using PTLC to obtain the pure diaryl ether. All compounds were characterized
1
by H-NMR, HRMS or elemental analysis, EI-MS and m.p.
o
1
4
-(4’-Chlorophenoxy)nitrobenzene (4a). White solid; m.p. 75.8-76.1 C; H-NMR: δ = 7.00 (4H, m),
+
7
.38 (2H, dd, J = 6.8, 2.4 Hz), 8.20 (2H, dd, J = 7.2, 2.4 Hz); HRMS-FAB: m/z [M+NH
4
] Calcd. for
12 12 2 3
C H N O
Cl: 267.0531; found: 267.0532.
o
1
4
-(3’-Methylphenoxy)nitrobenzene (4b). White solid; m.p. 61.9-62.2 C; H-NMR: δ = 2.78 (3H, s),
6
.88 (2H, m), 6.99 (2H, d, J = 9.2 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.29 (1H, t, J = 8.0 Hz), 8.18 (2H, d,
+
J = 9.2 Hz); HRMS-FAB: m/z [M+NH
4
] Calcd. for C13
H
15
N
2
O
3
: 230.0812; found: 230.0811.
o
1
4
-(2’-Chlorophenoxy)nitrobenzene (4c). White solid; m.p. 76.8-77.0 C; H-NMR: δ = 6.93 (2H, m),
.16 (1H, dd, J = 8.0, 1.6 Hz), 7.23 (1H, dt, J = 8.0, 1.6 Hz), 7.33 (1H, dt, J = 8.0, 1.6 Hz), 7.51 (1H,
7

Molecules 2007, 12
865
+
dd, J = 8.0, 1.6 Hz), 8.19 (2H, m); HRMS-FAB: m/z [M+NH ] Calcd. for C H N O Cl: 267.0531;
4
12 12
2
3
found: 267.0529.
o
1
4
-(4’-tert-Butylphenoxy)nitrobenzene (4d). White solid; m.p. 61.2-61.6 C; H-NMR: δ = 1.35 (9H, s),
+
6
.99 (4H, m), 7.41 (2H, m), 8.18 (2H, d, J = 8.8 Hz); HRMS-FAB: m/z [M+NH
4
] Calcd. for
C H N O : 289.1547; found: 289.1546.
1
6
21
2
3
o
1
4
-(4’-Nitrophenoxy)nitrobenzene (4e). Pale yellow solid; m.p. 144.5-144.9 C; H-NMR: δ = 7.15 (4H,
+
m), 8.28 (4H, m); GC/MS (EI, 70eV): m/z (%) = 260 (M , 100), 230 (40), 139 (65.1); Anal. calcd. for
12 8 2 5
C H N O : C, 55.39; H, 3.10; N, 10.77. Found: C, 55.21; H, 3.36; N, 10.66.
o
1
4
-(Phenoxy)nitrobenzene (4f). White solid; m.p. 55.9-56.3 C; H-NMR: δ = 6.99 (2H, d, J = 12 Hz),
7
.08 (2H, d, J = 8.4 Hz), 7.24 (1H, t, J = 6.8 Hz), 7.41 (2H, t, J = 8.4 Hz), 8.18 (2H, d, J = 12 Hz);
+
GC/MS (EI, 70eV): m/z (%) = 215 ( M , 100 ), 185 (24.9), 77(62.2); Anal. calcd. for C H NO : C,
1
2
9
3
6
6.97; H, 4.18; N, 6.51. Found: C, 66.75; H, 4.36; N, 6.58.
1
2
-(4’-Chlorophenoxy)nitrobenzene (4g). Pale yellow liquid; H-NMR: δ = 6.96 (3H, m), 7.21 (1H, t, J
8.0 Hz), 7.31 (2H, m), 7.51 (1H, dt, J = 8.4, 1.6 Hz), 7.95 (1H, dd, J = 8.4, 1.6 Hz); GC/MS (EI,
=
+
+
7
0eV): m/z (%) = 251 (M , 10.8), 249 (M , 32.5), 122 (100); Anal. calcd. for C12
8 3
H NO Cl: C, 57.73;
H, 3.23; N, 5.61. Found: C, 57.62; H, 3.29; N, 5.54.
1
2
-(4’-tert-Butylphenoxy)nitrobenzene (4h). Yellow liquid; H-NMR: δ = 1.32 (9H, s), 6.97 (2H, d, J =
8
.8 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.14 (1H, t, J = 7.6 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.45 (1H, m), 7.92
+
(1H, d, J = 8.0 Hz); HRMS-FAB: m/z [M+NH
4
] Calcd. for C16
H
21
N
2
O
3
: 289.1547; found: 289.1552.
1
2
-(2’-Chlorophenoxy)nitrobenzene (4i). Pale yellow liquid; H-NMR: δ = 6.83 (1H, dd, J = 8.4, 1.2
Hz), 7.07 (1H, dd, J = 8.0, 1.6 Hz ), 7.16 (3 H, m), 7.47 (2H, m), 7.97 (1H, dd, J = 8.0, 1.6 Hz);
+
HRMS-FAB: m/z [M+NH
4
] Calcd. for C12
H
12
N
2
O
3
Cl: 267.0531; found: 267.0535.
1
2
-(3’-Methylphenoxy)nitrobenzene (4j). Pale yellow liquid; H-NMR: δ = 2.34 (3H, s), 6.83 (2H, m),
6
.99 (2H, m), 7.15 (1H, t, J =7.6 Hz), 7.23 (1H, t, J = 8.0 Hz), 7.46 (1H, dt, J = 8.0, 1.6 Hz), 7.93 (1H,
+
dd, J = 7.6, 1.6 Hz ); HRMS-FAB: m/z [M+NH
4
] Calcd. for C13
H
15
N
2
O
3
: 247.1077; found: 247.1080.
1
2
-(4’-tert-Butylphenoxy)benzonitrile (4k). White liquid; H-NMR: δ = 1.33 (9H, s), 6.84 (1H, d, J =
8
.8 Hz), 7.00 (2H, m), 7.08 (1H, t, J = 7.2 Hz), 7.39 (3H, m), 7.63 (1H, dd, J = 7.6, 1.6 Hz); HRMS-
+
FAB: m/z [M+NH
4
] Calcd. for C17
H
21
N
2
O: 269.1648; found: 269.1648.
o
1
2
-(4’-Chlorophenoxy)benzonitrile (4l). White solid; m.p. 85.0-85.7 C; H-NMR: δ = 6.85 (1H, d, J =
8
.8 Hz), 7.01 (2H, m), 7.14 (1H, t, J = 7.2 Hz), 7.35 (2H, m), 7.47 (1H, m ), 7.66 (1H, dd, J = 8.0, 2.0
+
Hz); HRMS-FAB: m/z [M+NH
4
] Calcd. for C13
H
12
N
2
OCl: 247.0627; found: 247.0633.

Molecules 2007, 12
866
Acknowledgements
This work was supported by the program for New Century Excellent University Talents (NCET),
State Education Ministry of China, the Scientific Research Foundation for Returned Overseas Chinese
Scholars, State Education Ministry of China (No.14110101), the Key Project of Chinese Ministry of
Education (No.107105) and the Science & Technology Research Plan in Shaanxi Province of China
(
No.2006K01-G31-04). We also acknowledge Northwest A&F University for the financial assistance
within the Program for Excellent Young Talents (No. 01140301 and 01140402).
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2007 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.
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