Solvent-free synthesis of aryl ethers promoted by tetrabutylammonium fluoride

Article abstract of DOI:10.3184/030823410X12791804205820

The reaction of aryl fluorides with silyl reagents has been shown to be efficiently promoted by tetrabutylammonium fluoride, providing aryl ethers with good to excellent yields under solvent-free conditions. The efficiency of this reaction was demonstrate

Full text of DOI:10.3184/030823410X12791804205820

JOURNAL OF CHEMICAL RESEARCH 2010
JULY, 395–398
RESEARCH PAPER 395
Solvent-free synthesis of aryl ethers promoted by tetrabutylammonium
fluoride
Wei Xiong , Quansheng Ding , Jiuxi Chen *, Jinchang Ding and Huayue Wua
a
a
a
a,b
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. China
bWenzhou Vocational andTechnical College, Wenzhou 325035, P. R. China
The reaction of aryl fluorides with silyl reagents has been shown to be efficiently promoted by tetrabutylammonium
fluoride, providing aryl ethers with good to excellent yields under solvent-free conditions. The efficiency of this reac-
tion was demonstrated by the compatibility with aldehyde, nitro, cyano and acetyl groups. Moreover, the rigorous
exclusion of air/moisture was not required in these transformations which proceeded under milder conditions than
previously reported reactions of this type.
Keywords: tetrabutylammonium fluoride, aryl ethers, solvent-free conditions
Aryl ethers are important functional groups. The recent publi-
cation of several total syntheses of vancomycin aglycon has
further focused attention on the importance of new technology
reaction. Obviously, the presence of additional solvents makes
the reaction rate lower (entries11–17). So we choose to
perform this reaction under solvent-free conditions. The yield
1
,2
for the construction of the aryl ether unit. The classical
Ullmann ether synthesis remains an important tool in aryl ether
was decreased to some extent when the amount of TBAF·3H O
2
was decreased to 0.6 equiv. or 0.8 equiv. (entries 18–19).
The general efficiency of this protocol was then studied for
the synthesis of a variety of aryl ethers. As shown in Table 2,
the reaction proceeded smoothly in the presence of a variety of
functional groups including aldehyde, nitro, cyano and acetyl
groups under the optimised conditions. Nitro-substituted
aryl fluorides reacted with silyl reagents easily and gave aryl
ethers in high yield because the electron withdrawing group
increased the reactivity of the aryl fluorides. For example,
4-nitrofluorobenzene (1b) reacted quickly to generate the
corresponding aryl ether, 1-methoxy-4-nitrobenzene (3b),
in almost quantitative yield in 0.5 hour (Table 2, entries 2
and 7).
Steric hindrance of an aryl fluoride was also well accom-
modated. The reaction of ortho-substituted aryl fluoride,
such as 2-fluorobenzaldehyde (1d) with 2a produced 2-
methoxybenzaldehyde (3d) in 85% isolated yield (Table 2,
entry 4). Unfortunately, attempts to use less activating meta-
substituted aryl fluorides such as 3-fluorobenzaldehyde with
tetramethyl orthosilicate produced 3-methoxybenzaldehyde
(3i) in 41% yield. However, the reaction of electron-rich and
electron- neutral aryl fluoride with tetramethyl orthosilicate
was unsuccessful under the standard conditions. Note that the
3,4
synthesis. In addition, several other methods have also been
5,6
reported. Recently, KF/Al O -mediated S Ar addition of aryl
2
3
N
alcohols to electron-deficient aryl halides in the presence of
8-crown-6 was shown to be an efficient alternative to ether
1
7,8
synthesis. Potentially efficient methods for the synthesis of
aryl ethers from protected alcohols rather than from the parent
alcohols have also been described.
9
–13
A variety of reagents
have been used to promote the deprotection of the silyl group,
9
10,11
12
including CsF, anhydrous TBAF
phosphazenes or
1
3
proazaphosphatranes. These protocols all use trialkylsilyl-
protected aryl alcohols. As such, these reactions produce one
equivalent of silicon by-product relative to the amount of
aryl ether formed. Love reported that tetraphenoxysilane
and tetraalkoxysilanes react readily with aryl fluorides in
the presence of anhydrous TBAF in THF and acetone in a
1
4
dry N atmosphere. However the novel method was only suc-
2
cessful with the highly reactive 2,4-dinitrofluorobenzene, 2-
fluorobenzonitrile, 5-chloro-2,4,6-trifluoropyrimidine. Alde-
hydes were unreactive. Additionally, it was carried out in
volatile organic solvent for long reaction time in a dry N2
atmosphere. Therefore, the development of facile and environ-
ment friendly methods for the synthesis of aryl ether is a useful
aspect of organic synthesis.
2
,4-dimethoxy-1-nitrobenzene (3j) was obtained in 92% yield
Compared with the reactions in organic solvents, solvent-
free reactions are often rapid, regio- or chemoselective, occur
in high yields and have environmental and economic advan-
when the 2,4-difluoro-1-nitrobenzene (1f) was employed
(
Table 2, entry 9).
Furthermore, the present route to aryl ethers was success-
15–17
tages.
synthetic methodologies,
thesis of aryl ethers from the reaction of aryl fluorides with
In continuation of our interest in solvent-free
fully applied to a large scale reaction. For instance, the reac-
18–25
we report here solvent-free syn-
tion of 1a (1.24 g) with 2a (1.52 g) promoted by TBAF·3H O
2
provided the desired product 3a in 93% (Table 2, Entry 1).
tetra-alkoxysilanes in the presence of TBAF·3H O under mild
2
Finally, to extend the scope of TBAF·3H O-promoted
2
conditions.
method of aryl ethers formation under solvent-free condition,
trimethoxy(phenyl)silane (2c),methyltri(ethylmethylketoximo)
silane (2d) and vinyltri(methylethylketoxime)silane (2e) were
employed. As shown in Scheme 1, the reactions were also
performed smoothly and gave the corresponding products 3b
and butan-2-one-O-4-nitrophenyl oxime (3k) using the present
protocol with excellent yields.
In summary, a new protocol to synthesise aryl ethers has
been developed. Compared to previous reported methodolo-
gies, the presented protocol is not only very simple, quick
but also greatly decreases environmental pollution. The reac-
tion did not need the protection of nitrogen nor argon, and
The model reaction of 4-fluorobenzaldehyde (1a) with
tetramethoxysilane (2a) was conducted to identify the optimal
reaction conditions. The results are listed in Table 1. Firstly,
the efficacy of various promoters was investigated. Entry 1
shows the blank reaction without the addition of any promot-
ers. In this case no desired product was obtained after 24 h.
Among all the promoters screened (tetrabutylammonium
bromide (TBAB), tetrabutylammonium iodide (TBAI), CsF,
LiF, CuF , NH F, KF·2H O and CeF ), TBAF·3H O was found
2
4
2
3
2
to be the most effective reagent in terms of reaction yields. The
desired product 4-methoxybenzaldehyde (3a) was obtained in
6
2% yield (entries 2–10). Encouraged by this result, we next
TBAF·3H O was much cheaper and safer than solution of
2
planned to determine the influence of solvent on the model
14
TBAF in THF. This protocol avoids the use of a hazardous
solvent, toxic metallic catalysts, and is of low cost. Further-
more, the present protocol can tolerate a wide variety of
*
Correspondent. E-mail: jiuxichen@wzu.edu.cn

3
96 JOURNAL OF CHEMICAL RESEARCH 2010
Table 1 Screening conditionsa
b
Entry
Reagent /equiv.)
Solvent
Yield /%
1
2
3
4
5
6
7
8
none
none
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
DMF
toluene
NRc
62
NR
NR
45
NR
NR
15
NR
NR
58
75
60
NR
NR
NR
92
2
TBAF·3H O (1.0)
TBAB (1.0)
TBAI (1.0)
CsF (1.0)
LiF (1.0)
CuF
NH F (1.0)
KF·2H O (1.0)
CeF (1.0)
2
(1.0)
4
9
2
1
1
1
1
1
1
1
1
1
1
2
a
0
1
2
3
4
5
6
7
8
9
0
3
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
TBAF·3H
2
O (1.0)
2
O (1.0)
2
O (1.0)
2
O (1.0)
2
O (1.0)
2
O (1.0)
2
O (1.0)
2
O (0.6)
2
O (0.8)
2
O (1.2)
CH
acetone
CH CN
2
ClCH
2
Cl
3
none
none
none
none
61
82
92
Reaction conditions: 4-fluorobenzaldehyde 1a (1.0 mmol), tetramethyl orthosilicate 2a (0.6 equiv.), reagent, solvent (3 mL), 9 h,
o
b
c
80 C. Isolated yield. NR = No reaction.
2
9
1
functional groups, including aldehyde, nitro, cyano and acetyl
groups.
2-Methoxybenzaldehyde (3d): Colourless oil; H NMR (300 MHz,
CDCl ): δ (ppm) 3.89 (s, 3H, CH ), 6.94–6.99 (m, 2H, ArH), 7.51–
3
3
13
7
.52 (m, 1H, ArH), 7.78–7.80 (m, 1H, ArH), 10.44 (s, 1H, CHO);
C
NMR (75 MHz, CDCl ): δ (ppm) 55.4, 111.4, 120.4, 124.6, 128.2,
3
Experimental
1
35.8, 161.6, 189.6.
-(4-Methoxyphenyl)ethanone (3e): Pale yellow oil; H NMR
(300 MHz, CDCl ): δ (ppm) 2.55 (s, 3H, CH CO), 3.88 (s, 3H, CH O),
Chemicals were purchased and used without further purification. All
the melting points were uncorrected. NMR spectroscopy was per-
formed on a Bruker-300 spectrometer using CDCl as the solvent with
tetramethylsilane (TMS) as an internal standard at room temperature.
Chemical shifts are given in δ relative to TMS, the coupling constants
J are given in Hz. Mass spectra (EI, 70 eV) were measured with
SHIMADZU GCMS-QP2010 Plus. Elemental analyses were carried
out using a Carlo-Erba EA1108 instrument. Column chromatography
was performed using EM Silica gel 60 (300–400 mesh).
1
30
1
3
3
3
13
3
6.93 (d, 2H, J = 8.9 Hz, ArH), 7.94 (d, 2H, J = 8.9 Hz, ArH);
NMR (75 MHz, CDCl ): δ (ppm) 26.1, 55.3, 113.5, 130.1, 130.4,
163.3, 196.6; IR (KBr): νmax/cm 3065, 3002, 2950, 2843, 1675, 1597,
C
3
−
1
1510, 1425, 1359, 1258, 1175, 1115, 1026, 958, 834, 579.
4-Ethoxybenzonitrile (3f): Pale yellow solid, m.p. 51–53 °C; H
31
1
NMR (300 MHz, CDCl ): δ (ppm) 1.44 (t, 3H, J = 7.0 Hz, CH ), 4.08
3
3
(
q, 2H, J = 7.0 Hz, CH ), 6.93 (d, 2H, J = 8.7 Hz, ArH), 7.58 (d, 2H,
2
13
J = 8.7 Hz, ArH); C NMR (75 MHz, CDCl ): δ (ppm) 14.6, 63.9,
3
−
1
Preparation of aryl ethers; general procedure
The aryl fluorides (1.0 mmol) and tetraalkoxysilanes (0.6 equiv.), and
103.7, 115.2, 119.3, 134.0, 162.3; IR (KBr): νmax/cm 3074, 2983,
2935, 2895, 2221, 1603, 1504, 1394, 1299, 1255, 1168, 1112, 1036,
917, 833, 702, 499.
TBAF·3H O (1.0 equiv.) were placed in a Schlenk reaction tube and
2
32
1
4
-Ethoxybenzaldehyde (3g): Colourless oil; H NMR (300 MHz,
stirred for given time at 80 °C. After completion of the reaction, as
indicated by TLC, the crude products were directly separated by
column chromatography using petroleum ether/EtOAc as eluent to
afford pure corresponding products.
CDCl ): δ (ppm) 1.43 (t, 3H, J = 7.0 Hz, CH ), 4.09 (q, 2H, J =
3
3
7
.0 Hz, CH ), 6.96 (d, 2H, J = 8.7 Hz, ArH), 7.80 (d, 2H, J = 8.7 Hz,
2
13
ArH), 9.85 (s, 1H, CHO); C NMR (75 MHz, CDCl ): δ (ppm) 14.5,
63.8, 114.6, 129.7, 131.9, 164.0, 190.7; IR (KBr): νmax/cm 3069,
3
−
1
2
6
1
4
-Methoxybenzaldehyde (3a): Colourless oil; H NMR (300 MHz,
2
926, 2858, 2736, 1690, 1599, 1508, 1255, 1161, 1112, 1040, 834.
1-Ethoxy-4-nitrobenzene (3h): Pale yellow solid, m.p. 55–56 °C;
CDCl ): δ (ppm) 3.80 (s, 3H, CH ), 6.92 (d, 2H, J = 8.7 Hz, ArH),
3
3
31
1
3
7
.76 (d, 2H, J = 8.7 Hz, ArH), 9.80 (s, 1H, CHO); C NMR (75 MHz,
1
H NMR (300 MHz, CDCl ): δ (ppm) 1.45 (t, 3H, J = 7.0 Hz, CH ),
3
3
CDCl ): δ (ppm) 55.5, 114.3, 129.9, 131.9, 164.6, 190.8; IR (KBr):
3
4
2
6
2
6
.12 (q, 2H, J = 7.0 Hz, CH ), 6.93 (d, 2H, J = 9.0 Hz, ArH), 8.16 (d,
νmax/cm−1 3068, 2938, 2838, 2739, 1689, 1598, 1511, 1454, 1313,
2
13
H, J = 9.0 Hz, ArH); C NMR (75 MHz, CDCl ): δ (ppm) 14.5,
3
1
259, 1161, 1108, 1025, 835, 602, 512.
−1
4.4, 114.4, 125.8, 141.3, 164.0; IR (KBr): νmax/cm 3111, 2987,
27
1
1
-Methoxy-4-nitrobenzene (3b): White solid, m.p. 51–52 °C; H
938, 1592, 1497, 1397, 1333, 1254, 1173, 1103, 1034, 911, 852, 755,
45.
NMR (300 MHz, CDCl ): δ (ppm) 3.91 (s, 3H, CH ), 6.96 (d, 2H,
J = 9.2 Hz, ArH), 8.20 (d, 2H, J = 9.2 Hz, ArH); C NMR (75 MHz,
3
3
13
23
1
3
-Methoxybenzaldehyde (3i) : Colourless oil; H NMR (300 MHz,
−
1
CDCl ): δ (ppm) 55.8, 113.9, 125.7, 141.3, 164.5; IR (KBr): νmax/cm
3
CDCl ): δ (ppm) 3.85 (s, 3H, CH ), 7.17–7.18 (m, 1H, ArH), 7.37–
3
3
3
1
025, 2973, 2938, 2842, 1591, 1501, 1459, 1334, 1261, 1173, 1105,
017, 847, 749, 690, 618.
13
7
.44 (m, 3H, ArH), 9.96 (s, 1H, CHO); C NMR (75 MHz, CDCl ):
3
δ (ppm) 55.3, 111.8, 121.3, 123.3, 129.8, 137.6, 159.9, 192.0
2
8
1
4
-Methoxybenzonitrile (3c): White solid, m.p. 56 °C; H NMR
27
2
,4-Dimethoxy-1-nitrobenzene (3j): Pale yellow solid, m.p. 69 °C;
1
(
300 MHz, CDCl ): δ (ppm) 3.86 (s, 3H, CH ), 6.95 (d, 2H, J =
H NMR (300 MHz, CDCl ): δ (ppm) 3.90 (s, 3H, CH ), 3.96 (s, 3H,
3
3
1
3
3
3
13
8
.9 Hz, ArH), 7.59 (d, 2H, J = 8.9 Hz, ArH); C NMR (75 MHz,
CH ), 6.50–6.54 (m, 2H, ArH), 8.01 (d, 1H, J = 8.8 Hz, ArH); C
3
CDCl ): δ (ppm) 55.3, 103.8, 114.5, 119.0, 133.8, 162.6; IR (KBr):
NMR (75 MHz, CDCl ): δ (ppm) 55.9, 56.5, 99.6, 104.7, 128.5, 132.9,
3
3
νmax/cm− 3072, 2938, 2842, 2221, 1602, 1505, 1453, 1300, 1257,
1
−1
155.7, 164.8; IR (KBr): νmax/cm 3035, 2986, 2850, 1609, 1545, 1449,
1
170, 1023, 832, 680, 547.
1344, 1301, 1251, 1153, 1105, 847, 749.

JOURNAL OF CHEMICAL RESEARCH 2010 397
Table 2 Solvent-free synthesis of aryl ethersa
b
Entry
1
Ar-F
R2
Time /h
9
Product
Yield /%
92 (93)c
OMe
3a
3b
3c
2
3
OMe
OMe
0.5
2
99
94
4
5
6
7
8
9
OMe
OMe
OEt
9
12
9
3d
3e
3f
85
84
89
98
91
41
OEt
0.5
2
3g
3h
3i
OEt
OMe
12
10
OMe
2
3j
94d
a
b
Reactions conditions: ArF 1 (1.0 mmol), Silane 2 (0.6 equiv.), TBAF·3H2O (1.0 equiv.), 80 °C, solvent-free. Isolated yield.
c
4
2
-Fluorobenzaldehyde (20 mmol), aldehydes (12 mmol), TBAF·3H O (1.0 equiv.), 80 °C, solvent-free.
d
0.8 equiv. silane was used.
Scheme 1
Butan-2-one-O-4-nitrophenyl oxime (3k): Yellow solid, m.p. 35–
6 °C; anti:syn = 1:4 (ratio based on its H NMR spectrum), H NMR
14.9, 19.3, 23.4, 29.3 (6C, CH
(2C, Ph), 142.0 (C-NO , Ph), 164.3 (C=N), 164.8 (C-O, Ph); IR (KBr):
νmax/cm 3106, 2977, 2932, 1649, 1593, 1510, 1339, 1255, 1160,
2 3 3
CH , CH , anti + syn), 114.2, 125.7
1
1
3
(
1
2
−
1
300 MHz, CDCl ): δ (ppm) 1.16 (t, 3H, J = 7.7 Hz, anti, CH CH ),
3
2
3
+
.20 (t, 3H, J = 7.5 Hz, syn, CH CH ), 2.04 (s, 3H, anti, CH ), 2.07
1106, 898, 847, 751, 679; MS (EI, 70 eV): m/z (%) = 208 (M , 26),
2
3
3
(
s, 3H, syn, CH ), 2.38 (q, 2H, J = 7.5 Hz, syn, CH ), 2.55 (q, 2H,
139 (30), 109 (39), 93 (15), 81 (18), 70 (100), 63 (63), 54 (18); Anal.
3
2
J = 7.7 Hz, anti, CH ), 7.26 (d, 2H, J = 9.3 Hz, ArH), 8.19 (d, 2H,
Calcd for C10
H, 5.90; N, 13.22%.
H N O : C, 57.68; H, 5.81; N, 13.45. Found: C, 57.58;
12 2 3
2
13
J = 9.3 Hz, ArH); C NMR (75 MHz, CDCl ): δ (ppm) 10.2, 10.6,
3

3
98 JOURNAL OF CHEMICAL RESEARCH 2010
1
5
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Received 25 March 2010; accepted 7 June 2010
Paper 1000028 doi: 10.3184/030823410X12791804205820
Published online: 28 July 2010
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