Selective displacement of aryl fluorides with hydroquinone: Synthesis of 4-phenoxyphenols

Article abstract of DOI:10.1016/j.tetlet.2005.09.025

The selective displacement of a variety of aryl fluorides with hydroquinone has been achieved to give substituted 4-phenoxyphenols 3. In some cases the addition of 18-crown-6 resulted in a significant rate enhancement, and the reactions could be carried out at lower temperature. One of these derivatives, 3a (X = Cl) was converted to 2-propyl-4-(4-chlorophenoxy)phenol 2a, a precursor to the PPARγ receptor agonist 1.

Full text of DOI:10.1016/j.tetlet.2005.09.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7823–7826
Selective displacement of aryl fluorides with hydroquinone:
synthesis of 4-phenoxyphenols
Benjamin F. Marcune,* Michael C. Hillier, Jean-Franc¸ois Marcoux and Guy R. Humphrey
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 29 June 2005; revised 6 September 2005; accepted 6 September 2005
Available online 21 September 2005
Abstract—The selective displacement of a variety of aryl fluorides with hydroquinone has been achieved to give substituted 4-phen-
oxyphenols 3. In some cases the addition of 18-crown-6 resulted in a significant rate enhancement, and the reactions could be carried
out at lower temperature. One of these derivatives, 3a (X = Cl) was converted to 2-propyl-4-(4-chlorophenoxy)phenol 2a, a precur-
sor to the PPARc receptor agonist 1.
Ó 2005 Elsevier Ltd. All rights reserved.
As part of a general program to prepare and evaluate a
series of selective peroxisome proliferator-activated
receptor-c (PPARc) agonists similar to 1a (Fig. 1), we
required quantities of the 2-propyl-4-(4-chlorophen-
oxy)phenol 2a, which was elaborated from 3a (X = Cl)
in three steps.1 The synthesis of 3a involved displace-
ment of 4-fluorobenzaldehyde with a 4-chlorophenol
followed by a Dakin-type oxidation and in situ hydroly-
sis according to a known process.2 In order to construct
these substrates in a more expeditious fashion, we envi-
sioned the direct SNAr displacement of 1-chloro-4-flu-
orobenzene (4a) with hydroquinone (5). This idea
presented two potential challenges, namely the displace-
ment of an unactivated aryl fluoride and the potential
for ÔtrimerÕ formation due to over arylation of hydroquin-
one.3 According to the literature, aryl fluorides with
strong electron withdrawing groups (e.g., NO2, CN,
and CHO) undergo fluoride displacement with phenol
quite easily;4 there are fewer examples with hydroquin-
one.5,6 On the other hand, to the best of our knowledge,
the displacement of aryl fluorides containing less electro-
negative substituents (e.g., Cl, Br, or H) with phenol or
hydroquinone does not work well.7 In this letter, we
wish to report our efforts towards the general synthesis
of 4-phenoxyphenols using this methodology, and the
subsequent conversion of 3a to 2a.
Investigation and optimization of the arylfluoride dis-
placement was carried out using 1-chloro-4-fluorobenz-
ene 4a and hydroquinone (5), and these results are
summarized in Table 1. When the reaction was run
using stoichiometric amounts of hydroquinone and
KO-t-Bu, no conversion was observed in various sol-
vents at reflux after 24 h (entries 1–3). However, when
the reaction was carried out in DMSO significant con-
version of starting material to product was observed,
but a large amount of the trimer 6a was also formed
(entry 4). Increasing the amount of hydroquinone and
base used (4 equiv each, entry 5) resulted in a dramatic
decrease in the presence of trimer and the product 3a
could be isolated in 96% yield after 24 h at 170 °C. If this
reaction was repeated at 100 °C, full conversion could be
achieved after 72h but the isolated yield of product was
lowered to 72%. The use of other high-boiling polar
solvents generally resulted in poor isolated yield of 3a
and increased trimer (6a) formation. Inorganic bases
(entries 11–13) provided product in very low yield due
to decomposition of starting material 4a.
During the course of these investigations, we found that
DMSO had the potential to undergo catalytic decompo-
sition at elevated temperatures (>140 °C) under the opti-
mized reaction conditions (Table 1, entry 5).8 Therefore,
in the interest of developing milder reaction conditions,
we examined the displacement of 4a with 5 at 100 °C
using 4 equiv of the cation complexing agent, 18-
crown-6 (Table 2).9 Under these conditions, the reaction
was driven to near completion after 24 h in good yield
(85%) and with minimal trimer formation (Table 2,
Keywords: Aryl fluorides; Hydroquinone; Fluoride displacement.
*
Corresponding author. Tel.: +1 732594 6159; fax: +1 732594
1499; e-mail: ben_marcune@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.025

7824
B. F. Marcune et al. / Tetrahedron Letters 46 (2005) 7823–7826
O
S
HN
O
O
O
HO
X
O
O
X
2a
1a
F
OH
O
+
X
HO
HO
X
5
4a: X = Cl
3a
Figure 1. Retro-synthesis of a PPARc agonist 1.
Table 1. Displacement of 4a with hydroquinone (5)
HO
F
O
O
Cl
conditions,
see table
+
+
Cl
OH
Cl
OH Cl
O
4a
5
3a
6a
Entry
Base
Base (equiv)
5 (equiv)
Solvent
Temperature (°C)
Time (h)
3a:6aa
3a Yield (%)
1
KO-t-Bu
t-Bu
1
1
1
1
4
4
4
4
4
4
4
4
4
1
1
1
1
4
4
4
4
4
4
4
4
4
Decane
MeCN
Toluene
DMSO
DMSO
DMSO
NMP
NMP
DMF
DMAc
DMSO
DMSO
DMSO
Reflux
Reflux
Reflux
170
170
100
170
170
Reflux
Reflux
170
24
24
24
24
24
7299:1
72
24
24
24
24
24
24
—
—
—
0
0
0
—
96
2KO-
3
4
5
6
7
8
9
10
11
12
13
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
NaO-t-Bu
KO-t-Bu
KO-t-Bu
K2CO3
65:35
98:2
72
72:28
92:8
96:4
82:18
92:8
80:20
96:4
42
37
23
39
16
8
NaOH
LiOH
170
170
30
a Product ratios determined by HPLC analysis.
entry 2). Similarly, compounds 4d,f, and 4g reacted
more quickly to give product at 100 °C in the presence
of the additive. On the other hand, substrates 4b,c,
and 4e showed no rate enhancement in the reaction with
5 with or without the crown ether at 100 °C. However,
substrates 4c and 4e could be converted to 6c and 6e
in better yield, 94% and 99% yield, respectively, when
18-crown-6 was employed.
With a reasonable synthesis of 4-(4-chlorophenoxy)-
phenol (3a) in hand, we wanted to convert this inter-
mediate to the key starting material 2a (Scheme 1).
Therefore, allylation of 3a with allyl bromide (1.4 equiv)
and K2CO3 (4 equiv) in refluxing acetone provided the
allylated species 11 in nearly quantitative yield after
removal of the inorganics by filtration and concentra-
tion. This material was taken on crude and subjected
to a Lewis acid promoted Claisen rearrangement
with Et2AlCl (1.3 equiv) to give 12 in >95% yield.11
Workup of this reaction involved quench with 6 N
HCl and removal of the resultant aluminum salts by
filtration. The crude product containing filtrate could
be used in the next reaction without purification after
removal of heptane. Hydrogenation of 12 in the tolu-
ene solution was accomplished using WilkinsonÕs cata-
lyst [RhCl(PPh3)3, 1 mol %] at 45 °C and 45 psi H2 to
give the reduced product 2a in 90% yield after
purification.12
Another aryl fluoride substrate, 1-fluoro-4-iodobenzene
(7), exhibited a unique reaction profile as shown in
Table 3. When the reaction of this compound with
hydroquinone was run at 170 °C the desired product 8
was isolated in low yield (1%) along with the iodide dis-
placed product 9 and the dehalogenated intermediate 10.
Clearly, these by-products arise from benzyne formation
via elimination of iodide under the reaction condi-
tions.10 When the displacement of 7 was run at a lower
temperature (100 °C) the desired product 8 was recov-
ered in 72% yield after 72 h. Utilization of the additive
18-crown-6 provided for a similar yield of 8 after 24 h
(71%), but elevated amounts of benzyne impurities
could be detected.
In summary, we have demonstrated the selective SNAr
displacement of a variety of aryl fluorides with hydro-
quinone (4 equiv) using KO-t-Bu (4 equiv) in DMSO

B. F. Marcune et al. / Tetrahedron Letters 46 (2005) 7823–7826
Table 2. Scope of the aryl fluoride displacement and effect of 18-crown-6
7825
F
O
O
R1
R2
HO
KOtBu (4 eq.),
+
+
18-crown-6,
DMSO
R1
R3
R1
R3
OH
R1
R3
O
OH
R2
R2
R2
R3
(4 eq.)
4a-g
5
3a-g
6a-g
Entry
4
R1
R2
R3
H
18-Crown-6 (equiv)
—
Time (h)
Temperature (°C)
3:6
3 Yield (%)
1
2a
3
4
5
6
7
8
9
10
11
12f
13
14
15
16
a
Cl
H
H
H
H
H
H
72100
99:1
72
Cl
4
4
2
100
99:1
100
85
b
b
c
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
—
4
—
4
—
—
4
—
4
—
—
4
—
4
24
24
24
24
24
72100
24
24
24
24
72100
24
24
24
98:2
99:1
97:3
97:3
96:4
91
80
89
94
80
100
100
100
170
c
H
d
d
d
e
Br
Br
Br
CF3
CF3
99:1
99:1
81
100
100
100
170
99:1
98:2
99:1
94:6
65
85
99
77
e
OCF
f
f
g
g
3
OCF3
OCF3
H
14
100
170
100
98:2
92:8
99:1
68
16
53
H
Table 3. Displacement of 1-iodo-4-fluorobenzene with hydroquinone
F
HO
O
O
KOtBu,
+
+
18-crown-6,
DMSO
I
OH
I
OH
F
OH
7
5
8
9
O
+
OH
10
Entry
18-Crown-6 (equiv)
—
Time (h)
24
Temperature (°C)
8:9:1
0
Yield (%)
8
1
170
65:13:22
1
2—
3
72 100
95:4:1
100
72
4
24
87:12:1
71
O
O
allyl bromide, K2CO3,
acetone, 80 C
˚
Cl
O
Cl
OH
11
95%
3a
1) Et2AlCl, toluene,
heptane, rt
>95%
2) 6N HCl, filter
RhCl(PPh3)3 (1 %),
H2, toluene,
O
O
Cl
OH
45 psi, 45 C
˚
Cl
OH
2a
90%
12
Scheme 1. Synthesis of 2-propyl-4-(4-chlorophenoxy)phenol 2a.
at elevated temperature with a minimum of trimer for-
mation. It was noted that a cation scavenger, 18-
crown-6, can significantly accelerate this transformation
in some cases, allowing for the reaction to be carried out
at lower temperatures. One of these derivatives, 3a, was
efficiently converted to 2-propyl-4-(4-chlorophen-
oxy)phenol 2a, an important intermediate in the synthe-
sis of the PPARc agonist 1.

7826
B. F. Marcune et al. / Tetrahedron Letters 46 (2005) 7823–7826
5. (a) Markley, L. D.; Tong, Y. C.; Dulworkth, J. K.;
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