One-pot syntheses of 2,6-diiododiaryl ethers from para-EWG-substituted phenols by diacetoxyiodobenzene

Article abstract of DOI:10.1007/s11164-015-2373-y

2,6-Diiododiaryl ethers are not only useful blocks to construct substituted diaryl ethers but are also characteristic drug precursors. In this research, a one-pot tandem oxidation of phenols substituted with electron-withdrawing group at the para position by excess diacetoxyiodobenzene is proven as a novel and efficient method for preparing 2,6-diiododiaryl ethers. Using this method, three new 2,6-diiododiaryl ethers, namely, methyl 3,5-diiodo-2-methoxy-4-phenoxybenzoate (2), methyl 3,5-diiodo-4-phenoxybenzoate (6), and 1-(2,6-diiodo-4-nitrophenoxy)benzene (7) were readily obtained from the corresponding phenols, and the yields were good.

Full text of DOI:10.1007/s11164-015-2373-y

Res Chem Intermed (2016) 42:5387–5394
DOI 10.1007/s11164-015-2373-y
One-pot syntheses of 2,6-diiododiaryl ethers from para-
EWG-substituted phenols by diacetoxyiodobenzene
De-Jun Zhou1,2 Shu-Qiang Yin2
•
•
Yun-Chang Fan1 Qiang Wang1
•
Received: 16 August 2015 / Accepted: 19 November 2015 / Published online: 8 December 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract 2,6-Diiododiaryl ethers are not only useful blocks to construct substi-
tuted diaryl ethers but are also characteristic drug precursors. In this research, a one-
pot tandem oxidation of phenols substituted with electron-withdrawing group at the
para position by excess diacetoxyiodobenzene is proven as a novel and efficient
method for preparing 2,6-diiododiaryl ethers. Using this method, three new 2,6-
diiododiaryl ethers, namely, methyl 3,5-diiodo-2-methoxy-4-phenoxybenzoate (2),
methyl 3,5-diiodo-4-phenoxybenzoate (6), and 1-(2,6-diiodo-4-nitrophenoxy)ben-
zene (7) were readily obtained from the corresponding phenols, and the yields were
good.
Keywords Diacetoxyiodobenzene Á Drug precursors Á Electron-withdrawing
group (EWG) Á 2,6-Diiododiaryl ethers Á Tandem oxidation
Introduction
Diaryl ethers are common structures in many natural products and are biologically
active compounds, with some of these compounds being recognized as potential
drugs [1–4]. In particular, 2,6-diiododiaryl ethers have received considerable
attention as promising skeletons for anticancer drug molecules (Fig. 1) [5, 6].
Furthermore, construction of diaryl ether structures is a very important step in the
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2373-y)
contains supplementary material, which is available to authorized users.
&
De-Jun Zhou
zhoudj@hpu.edu.cn; zhoudj@pha.u-toyama.ac.jp
1
2
School of Physics and Chemistry, Henan Polytechnic University, Jiaozuo 454000, China
Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani 2630,
Toyama 930-0194, Japan
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D.-J. Zhou et al.
Fig. 1 Sampling of potential
drugs containing the 2,6-
diiododiaryl ether core
syntheses of natural products, vancomycin, and other glycopeptide antibiotics
[7–11]. In spite of more than a century of attempting to determine efficient synthetic
routes to these compounds, production of substituted diaryl ethers for applications in
the pharmaceutical industry and life sciences still remains difficult [12, 13].
The classical metal catalytic cross-couplings of phenols and aryl halides have
become very useful and popular in recent years. However, all of them need
expensive reagents and harsh reaction conditions [14–17]. Although arylation of
phenols to construct substituted diaryl ethers using diaryl iodonium salts has been
reported recently, only one substrate substituted with electron withdrawing groups
(EWGs) at the para position was investigated [18].
The use of hypervalent iodine reagents has recently gained considerable attention
in organic syntheses [19–21]. Diacetoxyiodobenzene (DAIB) has been used for
synthesizing ortho-iodo-diaryl ethers in the presence of EWGs at the para position
from corresponding phenols [22–24]. Furthermore, iodobenzenes play an important
role in organic chemistry because of their broad application; iodobenzenes can be
transformed into different aromatic compounds via Suzuki, Negishi and Heck
reactions [25–27]. Although construction of 2,6-diiododiaryl ethers from diamine
diaryl ethers was reported in 2002, the route comprised three steps, and the total
yield was under 30 % [28]. In this context, we have developed an efficient one-pot
route to construct 2,6-diiododiaryl ethers from corresponding phenols substituted
with EWGs at the para position (Scheme 1).
Experimental
All chemical reagents were obtained from commercial suppliers (Aldrich, Kanto
Chemical, Tokyo Chemical Industry, Aladdin, Wako Pure Chemical Industries) and
used without further purification. Anhydrous solvents were obtained from
commercial protocols. All nonaqueous reactions were carried out under Ar
atmosphere. Thin layer chromatography (TLC) was performed on silica gel 60
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One-pot syntheses of 2,6-diiododiaryl ethers from para-EWG…
5389
Scheme 1 Our strategy for the
construction of 2,6-diiododiaryl
ethers from phenols in one-pot
tandem oxidation
F254 glass plates precoated with a 0.25 mm thickness of silica gel (Merck). Column
chromatography was carried out on Cica Silica Gel 60N (spherical, neutral, 40–50
1
or 63–210 lm). H and 13C NMR spectra were obtained on a Varian UNITY plus
1
300 (300 MHz for H and 75 MHz for 13C) instrument, with CDCl3, CD3OD or
DMSO-d6 as an internal reference. IR spectra were measured on a JNM FT/IR-
460Plus spectrometer. Mass spectra were recorded on a JEOL D-200, JEOL JMS-
GCmate II, SHIMAZU GC–MS–QP 500, or JEOL AX 505 spectrometer. Melting
points were taken with a Yanagimoto micro-melting point apparatus and are
uncorrected.
General procedure for the preparation of 2,6-diiododiaryl ethers from
the corresponding phenols
A mixture of phenols (1, 4, 5) (10 mg) and PhI(OAc)2 (5 equivalent) in MeOH
(5 mL) was stirred at room temperature for about 20 min until the substrates (1, 4,
5) disappeared completely, then NaOMe (five equivalent) was added and run at
40 °C for 1 h, then heated to reflux. After refluxing for 4–8 h, the reaction mixture
was quenched with saturated NaCl (10 mL), extracted with ethyl acetate
(10 mL 9 3), combined the organic layers, dried over MgSO4 and concentrated
in vacuum. The residue was purified by column chromatography on silica gel to
afford the desired products (2, 6, 7).
Methyl 2,4-diiodo-6-methoxy-3-phenoxybenzoate (2) The resultant residue was
purified by flash silica gel column chromatography (5 g, hexane:ethyl acet-
ate = 100:1–30:1) to afford the product (2) (23 mg, 82 %) as a white solid, mp
108–110 °C.
1
IR (KBr, cm-1) 2922, 2361, 1715, 1561, 1491, 1415, 1371, 1246, 1188; H NMR
(300 MHz, CDCl3): d = 3.93 (3 H, s), 3.95 (3 H, s), 6.78 (2 H, d, J = 7.80 Hz),
7.07 (1 H, t, J = 7.80 Hz), 7.31 (2 H, t, J = 7.80 Hz), 8.36 (1 H, s); 13C NMR
(75 MHz, CDCl3): d = 52.76 (q), 62.60 (q), 84.62 (s), 93.15 (s), 115.48 (d), 122.61
123

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D.-J. Zhou et al.
(d), 123.63 (s), 129.65 (d), 142.19 (d), 155.47 (s), 158.22 (s), 161.78 (s), 163.56 (s);
MS: 510 (M?); HRMS calcd for C15H12I2O4 509.8825, found 509.8802.
Methyl 3,5-diiodo-4-phenoxybenzoate (6) The resultant residue was purified by
flash silica gel column chromatography (5 g, hexane:ethyl acetate = 30:1–10:1) to
afford the product (6) (16 mg, 51 %) as a white solid, mp 133–134 °C.
1
IR (KBr, cm-1) 3071, 2947, 1723, 1489, 1457, 1272, 1195; H NMR (300 MHz,
CDCl3): d = 3.94 (3 H, s), 6.78 (2 H, d, J = 7.79 Hz), 7.08 (1 H, t, J = 7.79 Hz),
7.32 (2 H, t, J = 7.79 Hz), 8.52 (2 H, s); 13C NMR (75 MHz, CDCl3): d = 52.75
(q), 90.83 (s), 115.48 (d), 122.66 8d), 129.66 (d), 130.00 (s), 141.41 (d), 155.54 (s),
157.49 (s), 163.61 (s); MS: 480 (M?); HRMS calcd for C14H10I2O3 479.8719, found
479.8733.
1,3-Diiodo-5-nitro-2-phenoxybenzene (7) The resultant residue was purified by
flash silica gel column chromatography (5 g, hexane:ethyl acetate = 50:1–30:1) to
afford the product (7) (15.8 mg, 47 %) as a white solid, mp 128–130 °C.
1
IR (KBr, cm-1) 2924, 1523, 1346, 1243, 900, 755; H NMR (300 MHz, CDCl3):
d = 6.79 (2 H, d, J = 7.69 Hz), 7.11 (1 H, t, J = 7.69 Hz), 7.34 (2 H, t,
J = 7.69 Hz), 8.73 (2 H, s); 13C NMR (75 MHz, CDCl3): d = 90.58 (s), 115.49 (d),
123.14 (d), 129.84 (d), 135.25 (d), 145.20 (s), 155.16 (s), 159.35 (s); MS: 467 (M?);
HRMS calcd for C12H7I2NO3 466.8516, found 466.8525.
Results and discussion
The desired reaction was investigated using methyl 4-hydroxy-2-methoxybenzoate
(1) as the model substrate, and the results are shown in Table 1. Methanol was used
as reaction solvent in the initial experiments, and the reactions were refluxed
directly with DAIB (Table 1, entries 1–4). The desired product (2) did not appear,
but compound (3) was formed at 93 % yield when two equivalents of DAIB were
used (Table 1, entry 1). With increasing amounts of DAIB, the desired product yield
increased (Table 1, entries 1–3). However, continuing to increase the amounts of
DAIB did not afford better yield of products (Table 1, entry 4). Based on the results,
five equivalents of oxidant DAIB may be sufficient, and the desired product can be
obtained at 62 % yield. When the reaction was stirred at ambient temperature for
20 min and at 40 °C for 1 h, then subsequently heated to reflux, the desired product
(2) was obtained at 66 % yield (Table 1, entry 5). After testing other solvents
(DMF, MeCN, and AcOH), AcOH was considered as the best, and the desired
product was obtained at 75 % yield without any additives (Table 1, entries 6–8).
Furthermore, the use of nucleophilic additives revealed that both NaOAc (in AcOH)
and NaOMe (in MeOH) greatly benefited the reaction (Table 1, entries 9 and 10).
Using the optimal reaction conditions, substrates methyl 4-hydroxybenzoate (4)
and 4-nitrophenol (5) were treated with DAIB in NaOMe. The desired compounds
(6) and (7) were obtained at 51 and 47 % yields, respectively (Scheme 2).
Next, the mechanism underlying this reaction was studied, and the following
reactions were carried out. The phenols (1, 4 and 5) were treated with two
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One-pot syntheses of 2,6-diiododiaryl ethers from para-EWG…
5391
Table 1 Study the conditions for synthesis of methyl 3,5-diiodo-methoxy-4-phenoxybenzoate (2) from
methyl 4-hydroxy-2-methoxybezoate (1) with DAIB
Entry
DAIB/equiv.
Solv.
Time (h)
Yield/% of 2, 3
1a
2a
3a
4a
5b
6b
2
3
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
24
24
24
24
24
5
2, 93
43, 50
62, 36
61, 35
66, 21
1, 90
5
10
5
5
7b
8b
9b,c
10b,d
5
MeCN
AcOH
AcOH
MeOH
24
15
4
1, 88
5
75, 14
79, 3
5
5
6
82, 9
All the reactions were performed with 10 mg of (1) in 5 ml of solvent under argon
a
Refluxed directly
b
Before refluxing, the reactions were run at ambient temperature for 20 min and 40 °C over 1 h
After stirring 20 min at ambient temperature, five equivalent of NaOAc was added then heated to 40 °C
After stirring 20 min at ambient temperature, five equivalent of NaOMe was added then heated to
c
d
40 °C
Scheme 2 Syntheses of methyl 3,5-diiodo-4-phenoxy-benzoate (6) and 1,3-diiodo-5-nitro-2-phenoxy-
benzene (7) from the corresponding phenols
equivalents of DAIB to give phenyliodoniophenolates (10, 11 and 12) at nearly
quantitative yields. Compounds (10, 11 and 12) could be transformed to
iodophenols (13, 14 and 15) at reasonable yields. Simultaneously, ortho-iodo-
diaryl ethers (3, 8 and 9) were afforded as the by-products (Scheme 3).
As outlined in Table 2, the reaction mixture was run in methanol at room
temperature for 4 days. Phenyl iodoniophenolate (10) can be transformed into the
desired iodophenol (13) and the undesired iodo-diaryl ether (3) at 59 and 35 %
123

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D.-J. Zhou et al.
Scheme 3 Preparation of iodophenols (13, 14, 15) from corresponding phenols
Table 2 The reaction conditions for preparation of the compound (13) from the compound (10)
Entry
Additive
Temp. (°C)
Time
Yield/% of 13, 3
1
–
25
4 days
35 h
6 h
59, 35
57, 40
1, 81
2
–
40
3
–
Reflux
25
4
NaOMe
NaOMe
NaOMe
24
73, 19
70, 23
70, 23
5a
6a,b
40
1 h
40
1 h
Unless otherwise noted, all the reactions were performed with 10 mg of (10), 5 equivalent of NaOMe in
5 ml of MeOH under argon
a
The reactions were run at 40 °C for 1 h
The reaction was performed with 5 mg of (10), 5 equivalent of NaOMe in 2 ml of CD3OD
b
yields, respectively (Table 2, entry 1). The substrate disappeared rapidly under
heating conditions, but unfortunately the yield of the desired product (13) decreased
with increasing reaction temperature (Table 2, entries 2 and 3). In the presence of
sodium methoxide, the reaction was performed at room temperature for 24 h, and
the product (13) was obtained at 73 % yield (Table 2, entry 4). If the reaction was
run at 40 °C for 1 h, the desired product (13) was afforded at 70 % yield (Table 2,
entry 5). To check whether the anisole appeared as a by-product in this reaction,
deuterated methanol was used as a reaction solvent, and the reaction was analyzed
by NMR and MS spectroscopy without workup. As predicted, (methoxy-d3)benzene
was found in both spectra (Table 2, entry 6).
The amounts of iodophenols (13, 14 and 15) were sufficient, and we investigated
whether iodophenols could be converted into the desired 2,6-diiododiaryl ethers by
the oxidant DAIB. As shown in Scheme 1, the synthesized compounds (13, 14 and
15) were oxidized by DAIB, and compounds (2, 6 and 7) were obtained at normal
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One-pot syntheses of 2,6-diiododiaryl ethers from para-EWG…
5393
Scheme 4 Syntheses of 3,5-diiodo-2-methoxy-4-phenoxy-benzoate (2) methyl 3,5-diiodo-4-
phenoxybenzenoate (6) and 1,3-diiodo-5-nitro- 2-phenoxybenzene (7) from the corresponding
iodophenols
a
b
c
d
e
f
g
h
Fig. 2 The possible mechanism of the tandem oxidation reaction
yields (Scheme 4). However, when ortho-iodo-diaryl ethers (3, 8 and 9) were
treated with DAIB, the corresponding 2,6-diiododiaryl ethers did not appear.
Based on experiment results and those of previous reports [25–27], the possible
mechanism of the tandem oxidation reaction is shown in Fig. 2. Initially, the lone
pair of phenol attacks the iodine of DAIB, losing an acetic acid to form intermediate
a. Intramolecular electrophilic aromatic substitution reaction with the loss of an
acetate anion gives cation b. Deprotonation yields intermediate c, which reacts with
a nucleophilic solvent (methanol or acetic acid) to afford iodophenol d. Iodophenol
is then oxidized by the excess DAIB to obtain intermediate e. The phenyl group
shifts from iodine to oxygen through intermediate f, thereby producing the desired
product ortho-diiodo-diaryl ether g. However, intermediate c tends to form the
undesired iodo-diaryl ether h at high temperatures.
Conclusion
In this work, we developed an effective one-pot synthesis of 2,6-diiododiaryl ethers
from corresponding phenols, which were substituted with EWG at the para position
by tandem oxidation reaction with DAIB. Using this method, three 2,6-diiododiaryl
123

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D.-J. Zhou et al.
ethers with extensive usability were synthesized in good yields. Furthermore, based
on our results and those of previous reports, a possible mechanism is proposed. The
phenols were oxidized to 2,6-diiododiaryl ethers through two important interme-
diates, namely, phenyliodoniophenolates and iodophenols.
Acknowledgment We are grateful to the Doctor Initiative Foundation of Henan Polytechnic University
(72515/407) for financial support.
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