Applications of hypervalent iodine(III) reagents in constructing ortho-iodo aromatic ethers

Article abstract of DOI:10.1177/17475198211005385

A one-pot method for the synthesis of aromatic ethers using hypervalent iodine(III) reagents obtained from the corresponding iodoaryl compounds is developed. In this concise method, six diaryl ethers and three heterocyclic aromatic ethers are synthesized in good yields. Furthermore, possible mechanisms for the syntheses of the hypervalent iodine reagents and construction of the aromatic ethers are proposed.

Full text of DOI:10.1177/17475198211005385

1005385CHL0010.1177/17475198211005385Journal of Chemical ResearchYang-Yang et al.
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Research Paper
Journal of Chemical Research
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Applications of hypervalent iodine(III)
reagents in constructing ortho-iodo
aromatic ethers
https://doi.org/10.1177/17475198211005385
DOI: 10.1177/17475198211005385
journals.sagepub.com/home/chl
Zhai Yang-Yang, Wang Zhen-Hui, Gong Xue-Yun, Hou Bao-Hua,
Cui Xiao-Rui, Sun Yan-Feng, Wang Ke-Yang, Liu Peng-Wei,
Li Xue-Yan and Zhou De-Jun
Abstract
A one-pot method for the synthesis of aromatic ethers using hypervalent iodine(III) reagents obtained from the
corresponding iodoaryl compounds is developed. In this concise method, six diaryl ethers and three heterocyclic
aromatic ethers are synthesized in good yields. Furthermore, possible mechanisms for the syntheses of the hypervalent
iodine reagents and construction of the aromatic ethers are proposed.
Keywords
diaryl ethers, heterocyclic aromatic ethers, hypervalent iodine(III) compounds, mechanisms
Date received: 3 March 2021; accepted: 8 March 2021
iodine compounds 4–6, and the application of these com-
pounds for the construction of aromatic ethers.
Introduction
Hypervalent iodine(III) reagents have been known for over
a century, but these compounds have only recently been
applied extensively in many important organic transforma- Results and discussion
tions.1–3 Diaryl ethers are common structural features in
In our laboratory, we developed an efficient and inexpensive
numerous biologically active compounds and natural prod-
method for preparing diacetoxyiodoarenes10–12 in ideal yields
ucts, some of which are potential drugs. Numerous meth-
from corresponding iodoarenes with sodium perborate
ods have been developed to synthesize diaryl ethers, and
new routes for a wide range of biologically active com-
pounds have been devised.4–8 Heterocyclic aromatic ethers
Medical School, Henan Polytechnic University, Jiaozuo, P.R. China
are likely to exhibit higher potent biological activity than
the corresponding diphenyl ethers. However, many of the
reported methods for the synthesis of heterocyclic aromatic
ethers have limited efficiency.9 In this study, we report a
Corresponding author:
Zhou De-Jun, Medical School, Henan Polytechnic University, Jiaozuo
454000, P.R. China.
concise and efficient method for the preparation of trivalent Email: zhoudj@hpu.edu.cn
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Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and
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Journal of Chemical Research
Scheme 1. Preparation of diacetoxyiodoarenes.
Scheme 2. Construction of aromatic ethers.
tetrahydrate.13 The optimized method for the preparation of be oxidized to ortho-iodo aromatic ethers via diacetoxyi-
diacetoxyiodoarenes from iodoarenes is described in section odoarenes. The detail experiment of the preparation of
“Experimental” (Scheme 1). aromatic ethers is described in section “Experimental”
The ortho-iodo aromatic ethers can be synthesized (Scheme 2).
smoothly from the corresponding phenols with the diace-
A possible mechanism for the construction of diacetox-
toxyiodoarenes. In particular, the 4-pyridone also could yiodoarenes has been proposed based on the experimental

Yang-Yang et al.
3
Scheme 3. Possible mechanism for the construction of the diacetoxyiodoarenes.
Scheme 4. A possible mechanism for the formation of heterocyclic aromatic ethers.
results (Scheme 3). The starting material is oxidized to
an unstable intermediate iodosyl benzene a, which then
Conclusion
In this work, we report an efficient method for synthesis of
diacetoxyiodoarenes via intramolecular rearrangement, and
three diacetoxyiodoarenes were prepared smoothly via this
method. Then, the front freshly prepared compounds are
used to oxidize some phenols, and the corresponding six
diaryl ethers and three heterocyclic aromatic ethers are syn-
thesized in good yields. Both of the possible mechanisms of
preparing diacetoxyiodoarenes and constructing diaryl
ethers are proposed.
reacts with acetic anhydride to form intermediate b.
Intramolecular rearrangement then yields the diacetoxyio-
doarenes. Infrared spectroscopy and UV-Vis light spec-
troscopy data showed that all of the diacetoxyiodoarenes
existed in virtually ionic form.13
Based on the experiment results and previous reports,14
a possible mechanism for the formation of heterocyclic aro-
matic ethers is shown in Scheme 4. Initially, the lone pair of
the hydroxy group attacks the iodine of the diacetoxyio-
doarene, which loses an acetic acid to form intermediate c.
Intramolecular electrophilic aromatic substitution with loss
of an acetate anion then yields cation d. Next, aromatiza-
Experimental
tion forms the relatively stable intermediate e, and a subse- All chemical reagents were obtained from commercial sup-
quent shift of the phenyl group from iodine to oxygen then pliers (Aldrich, Tokyo Chemical Industry (TCI), Aladdin,
yields the heterocyclic aromatic ether.
Macklin, and Bidepharm Pure Chemical Industries) and

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Journal of Chemical Research
were used without further purification. Anhydrous solvents (KBr, cm−1): 3385, 3321, 2261, 1631, 1441, 1385, 1193;
were obtained via standard protocols. All non-aqueous MS-ES: m/z=336 (M+); HRMS-ES: m/z [M]+ calcd for
reactions were carried out under an Ar atmosphere. Thin- C11H13IO4: 335.9859; found: 335.9849.
layer chromatography (TLC) was performed on silica gel
60 F254 glass plates precoated with a 0.25-mm thickness of o-(Diacetoxyiodo)toluene (6). Yield: 92%; white solid;
silica gel (Yantai Jiangyou). Column chromatography was m.p. 100–102°C. 1H NMR (300MHz, CDCl3): δ 1.98 (6 H,
carried out on Cica Silica Gel 60N (spherical, neutral, 40– s), 2.72 (3 H, s), 7.22-7.28 (1 H, m), 7.50-7.52 (2 H, m),
1
50μm or 63–210μm). H and 13C NMR spectra were 8.16 (1 H, d, J=7.42Hz); 13C NMR (75MHz, CDCl3): δ
obtained on a Varian UNITY plus 300 (300MHz for 1H and 20.13 (q), 25.39 (q), 126.83 (s), 128.05 (d), 130.49 (d),
75MHz for 13C) instrument, with CDCl3 as the solvent an 132.37 (d), 136.82 (d), 140.20 (s), 175.94 (s). IR (neat,
d internal reference. IR spectra were measured on a JNM cm−1) 3435, 1649, 1614, 1367, 1293, 1011, 764, 669;
FTIR-460 Plus spectrometer. Mass spectra were recorded MS-ES: m/z=336 (M+); HRMS-ES: m/z [M]+ calcd for
on JEOL D-200, JEOL JMS-GCmate II, SHIMAZU C11H13IO4: 335.9859; found: 335.9851.
GC-MS-QP 500, or JEOL AX 505 spectrometers. Melting
points were recorded with a Yanagimoto micro melting Iodo-4-phenoxypyridine (7). Yield: 94%; colorless oil. 1H
point apparatus and are uncorrected.
NMR (300MHz, CDCl3): δ 6.56 (1H, d, J=5.77Hz), 7.09-
7.12 (2 H, m), 7.25-7.31 (1 H, m), 7.41-7.48 (2 H, m), 8.29
(1 H, d, J=5.77Hz), 8.86 (1 H, s); 13C NMR (75MHz,
CDCl3): δ 85.38 (s), 111.01 (d), 120.65 (d), 125.73 (d),
130.18 (d), 150.36 (d), 153.66 (s), 158.43 (d), 163.74 (s);
Optimized method for the preparation of
diacetoxyiodoarenes from iodoarenes
NaBO3·4H2O (10mmol) was slowly added portionwise IR (neat, cm−1): 3038, 2360, 1562, 1464, 1397, 1270, 1199,
over 30min to a stirred solution of iodoarene 1 (1mmol) in 882; MS-ES: m/z=297 (M+); HRMS-ES: m/z [M]+ calcd
Ac2O (1.5mL) and AcOH (99.5%, 1.5mL) under Ar at for C11H8INO: 296.9651; found: 296.9652.
55°C. The mixture was stirred at 55°C until the starting
material had disappeared completely (as confirmed by TLC 3-Iodo-4-(p-tolyloxy)pyridine (8). Yield: 91%; colorless
analysis). Water (20mL) was added and the reaction mix- oil. 1H NMR (300MHz, CDCl3): δ 2.37 (3 H, s), 6.53 (1 H,
ture was stirred at room temperature for 30min. A consider- d, J=5.77Hz), 6.97 (2 H, d, J=9.52Hz), 7.20 (2 H, d,
able amount of solid precipitates was observed. The solid J=9.52Hz), 8.25 (1 H, d, J=5.77Hz), 8.83 (1 H, s); 13C
was separated by filtration, washed with water (25mL), NMR (75MHz, CDCl3): δ 20.92 (q), 85.15 (s), 110.69 (d),
and dried under air at room atmosphere. The filtrate was 120.46 (d), 130.44 (d), 135.44 (s), 150.25 (d), 151.28 (s),
extracted with EtOAc (3 10mL).And the combined extracts 158.25 (d), 163.93 (s); IR (neat, cm−1): 3034, 1567, 1504,
were dried over anhydrous MgSO4 and filtered. The solvent 1462, 1271, 1201, 1016, 885; MS-ES: m/z=311 (M+);
was evaporated under reduced pressure. The combined HRMS-ES: m/z [M]+ calcd for C12H10INO: 310.9807;
crude products were purified by recrystallization from a found: 310.9799.
mixture of AcOH/H2O (1:1).
3-Iodo-4-(o-tolyloxy)pyridine (9). Yield: 95%; colorless
oil. 1H NMR (300MHz, CDCl3): δ 2.16 (3 H, s), 6.41 (1 H,
General procedure for the preparation of
aromatic ethers
d, J=5.49Hz), 7.03 (1 H, d, J=7.69Hz), 7.19-7.32 (4 H,
m), 8.28 (1 H, d, J=5.77Hz), 8.86 (1 H, s); 13C NMR
A mixture of 4-pyridone or substrate 10–12 (100mg) and (75MHz, CDCl3): δ 16.07 (q), 84.64 (s), 109.89 (d), 121.14
freshly prepared diacetoxyiodoarene (5 equiv.) in MeOH (d), 126.19 (d), 127.55 (d), 130.26 (s), 131.87 (d), 150.12
(5mL) was refluxed for 4–8h. The reaction mixture was (d), 151.54 (s), 157.96 (d), 163.42 (s); IR (neat, cm−1):
quenched with saturated NaCl (10mL) and extracted with 3035, 2360, 1563, 1464, 1271, 1181, 888; MS-ES: m/z=311
ethyl acetate (3×10mL). The organic layers were com- (M+);HRMS-ES:m/z[M]+ calcdforC12H10INO:310.9807;
bined, dried over MgSO4, and concentrated under vacuum. found: 310.9791.
The residue was purified by column chromatography on
silica gel to afford the desired product.
Methyl 3-iodo-4-(p-tolyloxy)benzoate (13). Yield: 85%;
colorless oil. 1H NMR (300MHz, CDCl3): δ 2.36 (3 H, s),
Diacetoxyiodobenzene (4). Yield: 91%; white solid; m.p. 3.90 (3 H, s), 6.72 (1 H, d, J=8.52Hz), 6.95 (2 H, d,
161–163°C (lit.15161.2–162.2°C). 1H NMR (300MHz, J=7.97Hz), 7.19 (2 H, d, J=7.97Hz), 7.89 (1 H, dd,
CDCl3): δ 1.98 (6 H, s), 7.46 (2 H, d, J=7.6Hz), 7.58 (1 H, J=8.52, 1.92Hz), 8.52 (1 H, d, J=1.92Hz); 13C NMR
td, J=7.6Hz, J=1.1Hz), 8.08(2H, dd, J=7.6Hz, J=1.1Hz); (75MHz, CDCl3): δ 20.91 (q), 52.26 (q), 86.48 (s), 115.82
13C NMR (75MHz, CDCl3): δ 20.18 (q), 20.18 (q), 121.38 (d), 119.80 (d), 125.85 (s), 130.47 (d), 131.06 (d), 134.49
(s), 130.77 (d), 131.59 (d), 134.76 (d), 176.19 (s).
(s), 141.25 (d), 152.91 (s), 161.12 (s), 165.13 (s); IR (neat,
cm−1) 2863, 1720, 1588, 1505, 1477, 1433, 1253; MS-ES:
p-(Diacetoxyiodo)toluene (5). Yield: 89%; white solid; m/z=368 (M+); HRMS-ES: m/z [M]+ calcd for C15H13IO3:
m.p. 109–110°C. 1H NMR (300MHz, CDCl3): δ 1.97 (6 H, 367.9909; found: 367.9909.
s), 2.40 (s, 3 H), 7.27 (2 H, d, J=8.1Hz), 7.95 (2 H, d,
J=8.1Hz); 13C NMR (75MHz, CDCl3): δ 20.7 (q), 21.6 Methyl 5-iodo-2-methoxy-4-(p-tolyloxy)benzoate (14).
(q), 119.2 (s), 131.8 (d), 134.5 (d), 142.8 (s), 176.3 (s). IR Yield: 91%;white solid; m.p. 77–79°C. 1H NMR (300MHz,

Yang-Yang et al.
5
CDCl3): δ 2.36 (3 H, s), 3.69 (3 H, s), 3.87 (3 H, s), 6.35 (1 127.67 (d), 130.13 (s), 131.98 (d), 135.39 (d), 142.56 (s),
H, s), 6.94 (2 H, d, J=8.52Hz), 7.19 (2 H, d, J=8.52Hz), 152.32 (s), 162.06 (s); IR (neat, cm−1): 3093, 2359, 1574,
8.30 (1 H, s); 13C NMR (75MHz, CDCl3): δ 20.91 (q), 1518, 1462, 1341, 1258, 745; MS-ES: m/z=355 (M+);
52.08 (q), 56.18 (q), 75.09 (s), 101.54 (d), 116.12 (s), HRMS-ES: m/z [M]+ calcd for C13H10INO3: 354.9705;
119.36 (d), 130.46 (d), 134.28 (s), 142.43 (d), 152.98 (s), found: 354.9713.
161.10 (s), 161.31 (s), 164.50 (s); IR (neat, cm−1): 2948,
1687, 1588, 1505, 1438, 1276, 1103, 834; MS-ES: m/z=398 Declaration of conflicting interests
(M+); HRMS-ES: m/z [M]+ calcd for C16H15IO4: 398.0015;
found: 398.0010.
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
2-iodo-4-nitro-1-(p-tolyloxy)benzene (15). Yield: 79%;
colorless oil. 1H NMR (300MHz, CDCl3): δ 2.39 (3 H, s),
6.71 (1 H, d, J=9.07Hz), 6.98 (2 H, d, J=8.52Hz), 7.24 (2
H, d, J=8.52Hz), 8.10 (1 H, dd, J=9.07, 2.75Hz), 8.73 (1
H, d, J=2.75Hz); 13C NMR (75MHz, CDCl3): δ 20.97 (q),
85.66 (s), 114.63 (d), 120.22 (d), 125.13 (d), 130.77 (d),
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
The authors are grateful to the National Natural Science
Foundation of China (no. 81803399), the Science and Technology
135.33 (d), 135.51 (s), 142.66 (s), 152.17 (s), 162.78 (s); IR Research Project of Henan Province (nos 182102310300 and
(neat, cm−1): 3093, 2923, 1576, 1518, 1465, 1342, 1260893;
192102310144), and the Colleges and Universities in Henan
MS-ES: m/z=355 (M+); HRMS-ES: m/z [M]+ calcd for
C13H10INO3: 354.9706; found: 354.9713.
Province Key Scientific Research Project (nos 18A150028 and
19B350003) for the financial support.
ORCID iD
Methyl 3-iodo-4-(o-tolyloxy)benzoate (16). Yield: 89%;
colorless oil. 1H NMR (300MHz, CDCl3): δ 2.19 (3 H, s), Zhou De-Jun
3.90 (3 H, s), 6.54 (1H, d, J=8.79Hz), 6.97 (1 H, d,
https://orcid.org/0000-0002-9577-306X
J=7.69Hz), 7.14-7.31 (3 H, m), 7.87 (1 H, dd, J=8.79, References
1.92Hz), 8.54 (1 H, d, J=1.92Hz); 13C NMR (75MHz,
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CDCl3): δ 16.25 (q), 52.25 (q), 85.67 (s), 114.38 (d), 120.56
(d), 125.38 (d), 125.54 (s), 127.38 (d), 130.10 (s), 131.15
(d), 131.74 (d), 141.30 (d), 152.90 (s), 160.57 (s), 165.15
(s); IR (neat, cm−1): 2950, 2360, 1720, 1581, 1478, 1433,
1283, 1252, 1111; MS-ES: m/z=368 (M+); HRMS-ES: m/z
[M]+ calcd for C15H13IO3: 367.9909; found: 367.9910.
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1
Yield: 86%; colorless oil. H NMR (300MHz, CDCl3): δ
2.21 (3 H, s), 3.65 (3 H, s), 3.87 (3 H, s), 6.18 (1 H, s), 6.94
(1 H, d, J=7.97Hz), 7.12-7.31 (3 H, m), 8.32 (1 H, s); 13C
NMR (75MHz, CDCl3): δ 16.28 (q), 52.05 (q), 56.11 (q),
74.27 (s), 100.07 (d), 115.65 (s), 119.99 (d), 125.23 (d),
127.32 (d), 129.86 (s), 131.72 (d), 142.50 (d), 152.87 (s),
160.91 (s), 161.25 (s), 164.48 (s); IR (neat, cm−1): 2949,
2360, 1731, 1592, 1488, 1244, 1093, 781; MS-ES: m/z=398
(M+); HRMS-ES: m/z [M]+ calcd for C16H15IO4: 398.0015;
found: 398.0010.
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2-iodo-4-nitro-1-(o-tolyloxy)benzene (18). Yield: 85%;
colorless oil. 1H NMR (300MHz, CDCl3): δ 2.17 (3 H, s),
6.54 (1 H, d, J=9.07Hz), 7.01 (1 H, d, J=7.69Hz), 7.19-
7.34 (3 H, m), 8.09 (1 H, dd, J=9.07, 2.75Hz), 8.75 (1 H,
d, J=2.75Hz); 13C NMR (75MHz, CDCl3): δ 16.13 (q),
85.03 (s), 113.45 (d), 120.90 (d), 125.25 (d), 126.15 (d),