Practical synthesis of 2-iodosobenzoic acid (IBA) without contamination by hazardous 2-iodoxybenzoic acid (IBX) under mild conditions

Article abstract of DOI:10.3390/molecules26071897

We report a convenient and practical method for the preparation of nonexplosive cyclic hypervalent iodine(III) oxidants as efficient organocatalysts and reagents for various reactions using Oxone in aqueous solution under mild conditions at room temperature. The thus obtained 2-iodosobenzoic acids (IBAs) could be used as precursors of other cyclic organoiodine(III) derivatives by the solvolytic derivatization of the hydroxy group under mild conditions of 80 °C or lower temperature. These sequential procedures are highly reliable to selectively afford cyclic hypervalent iodine compounds in excellent yields without contamination by hazardous pentavalent iodine(III) compound.

Full text of DOI:10.3390/molecules26071897

molecules
Communication
Practical Synthesis of 2-Iodosobenzoic Acid (IBA) without
Contamination by Hazardous 2-Iodoxybenzoic Acid (IBX)
under Mild Conditions
Hideyasu China 1,2,*, Nami Kageyama , Hotaka Yatabe , Naoko Takenaga
2
2
3
and Toshifumi Dohi 2,*
1
Department of Medical Bioscience, Nagahama Institute of Bio-Science and Technology, 1266,
Tamuracho Nagahama-shi, Shiga 526-0829, Japan
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577,
Japan; ph0093ei@ed.ritsumei.ac.jp (N.K.); ph0090ir@ed.ritsumei.ac.jp (H.Y.)
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan;
ntakenag@meijo-u.ac.jp
2
3
*
Correspondence: h_china@nagahama-i-bio.ac.jp (H.C.); td1203@ph.ritsumei.ac.jp (T.D.)
Abstract: We report a convenient and practical method for the preparation of nonexplosive cyclic
hypervalent iodine(III) oxidants as efficient organocatalysts and reagents for various reactions us-
ing Oxone® in aqueous solution under mild conditions at room temperature. The thus obtained
2
-iodosobenzoic acids (IBAs) could be used as precursors of other cyclic organoiodine(III) deriva-
◦
tives by the solvolytic derivatization of the hydroxy group under mild conditions of 80 C or
lower temperature. These sequential procedures are highly reliable to selectively afford cyclic hy-
pervalent iodine compounds in excellent yields without contamination by hazardous pentavalent
iodine(III) compound.
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Citation: China, H.; Kageyama, N.;
Yatabe, H.; Takenaga, N.; Dohi, T.
Practical Synthesis of
®
Keywords: cyclic organoiodine(III) compounds; Oxone ; water, solvolytic functionalization, mild
2
-Iodosobenzoic Acid (IBA) without
Contamination by Hazardous
-Iodoxybenzoic Acid (IBX) under
Mild Conditions. Molecules 2021, 26,
897. https://doi.org/10.3390/
condition, metal-free, 2-iodosobenzoic acid
2
1
1. Introduction
molecules26071897
Cyclic hypervalent iodine reagents, such as 2-iodosobenzoic acid (IBA) and 2-iodoxybenzoic
acid (IBX) are nonmetallic green oxidants with excellent recyclability [1–3]. IBA and IBX can be
Academic Editor: Maged Henary
regenerated from 2-iodobenzoic acid (2-IB) without requiring an external ligand except for water
in this reoxidation step. This is because the carboxy group adjacent to the iodine atom serves
as an endogenous ligand. Recently, IBA, a representative trivalent cyclic hypervalent iodine
oxidant, has been used as a catalyst and reagent in various reactions, i.e., decarboxylative alkyny-
Received: 28 February 2021
Accepted: 24 March 2021
Published: 27 March 2021
lation [
C–H arylation [
tion [13], and asymmetric intramolecular
OAc [15 28], OMe [29 32], OTs [33 35], OTf [36
CF3 [55 56], OCOCF3 [57], alkynyl [58 62] ligands instead of the hydroxy group have also found
application in various reactions (Figure 1).
4
,
5
], decarboxylative acylarylation [
], C–H hydroxylation [10], C-H oxidation [11
-cyclopropanation [14]. IBA derivatives containing
37], Cl [38 42], F [43 45], CN [46], N3 [47 54],
6
], oxyalkenylation [
7
], oxyarylation [
8], oxidative
9
,12], ring-opening hydrazina-
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–
–
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Figure 1. 2-Iodosobenzoic acid (IBA) and its precursor 2-iodobenzoic acid (2-IB).
Although IBAs can be prepared from 2-IBs by existing methods (Figure 2) [63–66], the
development of a safer and more efficient method for their synthesis is highly desirable.
4
.0/).
Molecules 2021, 26, 1897. https://doi.org/10.3390/molecules26071897
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1897
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As shown in Figure 2, IBAs can be further oxidized to pentavalent cyclic hypervalent
IBXs [67], which need to be prevented for the preparation of IBAs [68
to the explosive nature of IBXs on heating and impact, while IBXs are useful in some
small-scale reactions [71 76]. Thus, contamination by IBX in the IBA products should be
–70], mainly due
–
avoided for long-term safe storage or large-scale use.
Figure 2. Synthesis of 2-iodosobenzoic acids (IBAs) and 2-iodoxybenzoic acids (IBXs) from 2-
iodobenzoic acids (2-IBs).
®
In recent decades, many reactions using Oxone , which is an inexpensive and com-
mercially available stable triple salt (2KHSO /KHSO /K SO ), have been developed
5
4
2
4
®
for practical synthetic purposes [77]. In particular, the use of Oxone as a re-oxidant
for pentavalent hypervalent iodine reagents is drawing attention for catalytic oxidation
reactions [78–92]. The reaction systems for alcohol oxidations [78–84] involving in situ gen-
erated active hypervalent iodine(V) species are optimized on the basis of the preparative
◦
conditions of IBX from 2-IB at 70 C [93]. Meanwhile, oxidative lactonizations from modi-
®
fied 2-IBs using Oxone occur at room temperature [85
of nonexplosive trivalent cyclic hypervalent iodines, i.e., IBA and its analogs, using Oxone
can be expected to provide a convenient and safe synthetic procedure; however, to best
–
87]. In this context, the generation
®
®
of our knowledge, the selective preparation of IBAs using Oxone has not been reported
so far.
Recently, we reported that IBAs generated in a reaction system containing 2-IB and
®
Oxone play a catalytic role in the selective oxidation of alkoxybenzenes to p-quinones [94].
This resulted in the development of the practical method herein reported for the selective
preparation of IBAs under mild conditions.
2. Results and Discussion
2.1. Selective Synthesis of IBA and Its Analogs
We started our investigation on the selective preparation of IBAs by evaluating the
®
solvent effects on the oxidation of 2-IB 1a using 1.0 equivalent of Oxone to obtain IBA
2a as a representative compound, and the results are summarized in Figure 3. First, the
reaction in water led to the successful production of IBA 2a in 82% yield (Figure 3, entry 2),
whereas IBA 2a was not produced in organic solvent in the absence of water (no reaction
®
because Oxone was not dissolved) (see entry 1). This result indicates that water plays
an essential role in the formation of IBA. Therefore, we assumed that an aqueous system
similar to the selective formation of p-quinone from alkoxybenzenes catalyzed by 2-IB 1a
®
with Oxone [94] could be suitable for the present reaction. We then investigated in detail
®
the effect of a series of organic solvents on the aqueous preparation of IBA 2a using Oxone .

Molecules 2021, 26, 1897
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Figure 3. Solvent effect on the selective synthesis of IBA 2a from 2-IB 1a using Oxone®.
Various water-miscible organic solvents were investigated to dissolve 2-IB 1a in this
reaction. The preparation of IBA 2a using acetonitrile (MeCN) in aqueous condition
(Figure 3, entry 3) was similar to that performed in the absence of organic solvents (Figure 3,
entry 2). Tetrahydrofuran (THF), dioxane, benzene and N,N-dimethylformamide (DMF)
were also examined, finding that the use of highly polar dioxane and DMF led to excellent
yields of IBA 2a (Figure 3, entries 5 and 7), whereas benzene, the least polar solvent among
these aprotic solvents, significantly reduced the yield of the desired product (Figure 3,
entry 6). The reason for this very low yield IBA formation was interpreted as being due
to that benzene forms a two-phase system and interferes with the dissolution of 2-IB into
water. Protic solvents such as MeOH, EtOH and 2,2,2-trifuoroethanol (TFE) gave IBA 2a
in high yields; however, they also worked as a ligand for IBA, causing the formation of
very small amounts of ligand-exchanged byproducts 3a–c (Figure 3, entries 8–10). The
white solid IBA 2a obtained after the water and acetone washings did not contain any other
byproducts. Although this result indicated that protic organic solvents were not suitable
for the selective preparation of IBAs, it also revealed that the IBA hydroxyl group could
undergo substitution reactions under mild conditions (vide infra). The yields indicated in
Figure 3 are almost equal to the conversion of 2-IB 1a.
®
Next, we investigated the substrate scope for the synthesis of IBAs using Oxone
under aqueous conditions with MeCN, and the results are shown in Figure 4. MeCN was
used as a component of the solvent to dissolve substrates
IBs, IBAs 2b containing fluoro-, chloro-, and bromo-substituents were smoothly obtained
in excellent yields from the corresponding halo-substituted 2-IBs 1b . From 2-IBs 1e
with electron-donating groups such as methyl-, methoxy-, and acethoxy-substituents (1e
and electron-withdrawing groups such as trifluoromethyl-, nitro- and cyano-substituents
1h ), the desired IBAs 2e were also produced in good yields. However, 2-IB bearing
1. By oxidation of 5-substituted 2-
–d
–
d
–j
–g)
(
–
j
–j
a hydroxy-substituent 1k afforded the desired product 2k in a moderate yield under
the same conditions. In the oxidation of 4-substituted 2-IBs, fluoro-, chloro-, bromo-,
trifluoromethyl-, and carboxy-substituted IBAs 2l
–p were obtained in excellent yields from
the corresponding 2-IBs 1l . In addition, the oxidized products of 4,5-disubstituted 2-IBs
–
p
containing difluoro-substituents 2q and dimethoxy-substituents 2r were obtained in high
yields. Meanwhile, with regard to 3-substituted 2-IBs, the reaction of methyl-substituted
®
1t
with a slight excess of Oxone afforded the expected IBA 2t in a good yield, whereas

Molecules 2021, 26, 1897
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the yield of bromo-substituted IBA 2s was lower even at the elevated temperature and
®
in the presence of a large excess of Oxone . Steric effects are probably important in the
3
formation of the cyclic
λ
-iodanes. Indeed, the presence of a substituent at the ortho position
of the iodine atom (3-position) interfered in the synthesis of the corresponding product
for 3-bromo-substituted 2-IB 1s. In the case of 6-substituted 2-IBs, fluoro-substituted
IBA 2u and methyl-substituted 2v were obtained in good yields. Finally, the reaction of
3
-iodonaphthalene-2-carboxylic acid
3 under the present conditions led to the expected
tricyclic hypervalent iodine compound 4 in an excellent yield (Scheme 1).
Figure 4. Substrate scope of the selective preparation of IBAs 2b
–
v
using Oxone® under aqueous
◦
®
conditions. (a) This reaction was performed at 30 C in the presence of 1.2 equivalents of Oxone . (b)
®
◦
Performed using 5 equivalents of Oxone at 40 C.
Scheme 1. Synthesis of tricyclic hypervalent iodine compound 4.
2.2. IBAs Synthesis Using Ferric Effect
As mentioned in Section 2.1, our present method can selectively afford trivalent cyclic
hypervalent iodine IBA at room temperature without contamination by pentavalent iodine
byproduct. The mild conditions used contributed favorably to this product selectivity.
Interestingly, we further found that iron ion in tap water (TW), which contained iron ion
(5.8 µM or less), contribute to the IBA formation, whereas calcium and magnesium ions as
main minerals in TW do not affect the selectivity. Indeed, IBA 2a was selectively produced
◦
from 2-IB 1a by heating even at 100 C in DW containing 5 mol% FeCl (Scheme 2, left).
3
On the other hand, IBX was instead formed as a main product in the absence of FeCl in
3

Molecules 2021, 26, 1897
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deionized water (DW) [93]. Other ferric salts such as Fe(NO ), Fe(OTf) , and FeSO had
3
3
4
similar effects. In addition, it was found that pentavalent IBX
5
was converted to IBA 2a in
◦
the presence of a catalytic amount of FeCl at 100 C (Scheme 2, right), while the formation
3
of unidentified high- and low-polar decomposition products were detected in the water and
the acetone washing solution, respectively. Here, 2-IB 1a was not produced. These results
would indicate that overoxidation of IBA 2a to pentavalent IBX
by ferric salts. Thus, the effect of the metal ion in the decomposition of hazardous IBX
5
was strongly prevented
is
5
also a significant key factor to ensure the safety for our trivalent cyclic hypervalent iodine
synthesis under heating conditions.
Scheme 2. Effect of a ferric salt on the selective synthesis of IBA 2a.
The reaction time in the synthesis of IBAs was significantly shortened by heating.
In the investigation of the heating conditions for the synthesis of IBA 2a in 0.2 M 2-IB
®
1a
in the presence of 2.5 mol% FeCl for 10 min, the required amount of Oxone and
3
◦
the reaction temperature were thus optimized to 60 C (Figure 5a) and 1.0 equivalent
(Figure 5b), respectively. The yield of IBA 2a was very sensitive to the reaction time, which
dropped from 83% for 10 min to 70% for 1 h. IBA may be decomposed to small molecules in
®
®
the presence of excess Oxone ; it has been reported that Oxone causes oxidative cleavage
®
of the aromatic ring [95]. Without Oxone , we also confirmed that IBA 2a was hardly
decomposed under the conditions of Scheme 2 in the presence of 1.0 equivalent of H SO
2
4
◦
and 10 mol% FeCl at 100 C for 10 min, while only 64% of IBA 2a was recovered by
3
®
replacing H SO in the presence of Oxone under the same conditions. Thus, the excess
uses of Oxone and performing the reaction at high temperature would decrease the IBA
yield as shown in Figure 5a,b.
2
4
®
Figure 5. Optimization of (
at 60 C for the synthesis of IBA 2a from 2-IB 1a in the presence of 2.5 mol% FeCl (MeCN/DW
a
) temperature using 1.0 equivalent of Oxone® and (
b
) amount of Oxone®
◦
3
(1/1)).

Molecules 2021, 26, 1897
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This optimized heating method could be applied to the synthesis of IBAs 2a
-IB 1a as well as the substrates 1b and 1g that are tolerable to over-oxidation at this
temperature were successfully converted to the desired IBAs 2a and 2g in high yields.
–j (Scheme 3).
2
–d
–j
–d
–j
However, the transformation of 2-IB having an electron-rich functional group, i.e., methoxy-
substituted 2-IB 1f, resulted in low yield of the corresponding IBA 2f due to the formation of
®
2
-carboxy-p-benzoquinone by the oxidation with Oxone . Therefore, in order to apply the
heating conditions, the stability of the product to oxidation must be considered.
FeCl (2.5 mol%, 5 mM)
3
O
83% ( R = H)
2a
21% (2f; R = OMe)
86% (2g R = OAc)
72% (2h; R = CF3)
75% (2i; R = NO2)
86% (2j; R = CN)

COOH Oxone (1.0 equiv.)
O
9
5% (2b; R = F)
8
5% (2c; R = Cl)
8
0% (2d; R = Br)
6
5% (2e; R = Me)
I
MeCN / DW (1/1)
I
OH
ο
6
0 C / 10 min
R
R
1a-j
2
a-j
Scheme 3. Short-time selective synthesis of IBAs 2a–j in the presence of ferric salt.
2.3. IBA Derivatives
As previously mentioned, when IBA 2a was synthesized in an aqueous solution with
alcohols, alkoxy-substituted derivatives 3a–c were obtained as byproducts by substitution
of the hydroxyl ligand of IBA 2a (see Figure 3), implying the potential of the solvolytic
ligand exchange of IBA 2a under mild conditions. For the ligand derivatization of IBAs,
the water molecule is an obstacle because the ligand exchanges of the IBA hydroxy group
are reversible. Thus, molecular sieves with a pore diameter of 3 Å (MS3Å) was used
for the solvolytic functionalization of IBA 2a in dehydrated protic solvent (Figure 6).
The quantitative derivatization to benziodoxole methoxide (IB-OMe) 6a was achieved by
◦
◦
heating IBA 2a at 60 C in MeOH (Figure 6, entry 1). Upon treatment at 80 C, benziodoxole
ethoxide (IB-OEt) 6b and benziodoxole 2,2,2-trifluoroethoxide (IB-OCH CF ) 6c were also
2
3
produced in high yields by the ligand exchange reaction with EtOH and TFE, respectively
n
(
Figure 6, entries 2 and 3). Benziodoxole n-propoxide (IB-O Pr) 6d was obtained in 98%
n
◦
i
yield using PrOH at 70 C (Figure 6, entry 4), and benziodoxole isopropoxide (IB-O Pr)
e was produced in 52% yield at 60 C in the presence of PrOH (Figure 6, entry 5). In the
cases of IB-O Pr 6d and IB-O Pr 6e, the temperature control was essential to suppress the
formation of a 2-IB-IBA condensate as a byproduct; here, the formation of 2-IB 1a can be
explained in terms of the alcohol oxidation by IBA. It is known that secondary alcohols are
readily oxidized by IBA [83]. No unwanted byproduct was found during the transformation
◦
i
6
n
i
to benziodoxole hexafluoroisopropoxide (IB-OCH(CF ) ) 6f using hexafluoroisopropanol
3
2
◦
(
HFIP) at 80 C (Figure 6, entry 6), which is most likely due to the stability of HFIP against
oxidation. Indeed, the condensate between 2-IB and IBA appeared during the reaction
n
n
for benziodoxole n-buthoxide (IB-O Bu) 6g using an oxidizable primary alcohol, BuOH,
◦
at 80 C, whereas such byproduct was not observed in the synthesis of benziodoxole
t
t
tert-buthoxide (IB-O Bu) 6h using BuOH as a solvent inert to oxidation. Nevertheless,
n
◦
IB-O Bu 6g could be selectively obtained by heat treatment at 60 C without the formation
of the condensate.
Using AcOH as a solvent, the solvolytic method was further applied to the synthesis of
benziodoxole acetate (IB-OAc) 7a and its analogs (R-IB-OAc) 7b
IBAs 2a (Scheme 4). IB-OAc 7a was easily produced in good yield by ligand exchange
of IBA 2a with AcOH at room temperature. Similarly, these transformations successfully
afforded R-IB-OAc 7b containing fluoro-, chloro-, and bromo-substituents; 7e with
–i from the corresponding
–
i
–
d
–g
electron-donating methyl-, methoxy-, and acethoxy-groups; and 7h and 7i bearing an
electron-withdrawing trifluoromethyl- and nitro-substituent, respectively.

Molecules 2021, 26, 1897
7 of 18
Figure 6. Benziodoxole alkoxides 6a–h by solvolytic functionalization of IBA 2a.
Scheme 4. Transformation of IBAs 2a–i to benziodoxole acetates 7a–i.
3. Materials and Methods
3.1. General Information
Substrates 1i
65] were prepared by Sandmeyer reaction of the corresponding anthranilic acids.
84] was synthesized by acetylation of compound 1k. Substrate 1j 103] is
[96], 1k [97], 1n [98], 1o [98], 1p [99], 1q [100], 1s [101], 1t [98], 1v [102],
and 3 [
Substrate 1g
[
[
1
13
19
derived from 5-bromo-anthranilic acid methyl ester. H, C, and F nuclear magnetic
resonance (NMR) spectra were recorded on ECS 400 and ECX 500 NMR spectrometers
(
(
JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-d6) or chloroform
CDCl ) as a solvent. Chemical shifts ( ) are reported in parts per million (ppm) relative
δ
3
1
13
to tetramethylsilane (
hexafluoroacetone (
δ
= 0 ppm) as an internal standard for H and C NMR spectra and
−
δ
=
84.6 ppm) as an internal standard for 19F NMR spectra. Coupling
constants (J) are reported in Hertz (Hz), and the multiplicity is reported according to
the following convention: singlet (s), doublet (d), double doublet (dd), double double
doublet (ddd), double triplet (dt), triplet (t), triple doublet (td), quartet (q), quintet (quin),
sextet (sext), septet (sep), and multiplet (m). Data are reported as follows: Chemical shift
(
number of protons, multiplicity, coupling constants). Infrared (IR) spectra were recorded
on a JASCO FT/IR-4200 spectrometer (JASCO Co., Tokyo, Japan) on diffuse reflectance
−
1
method using KBr powder. Absorptions are expressed in reciprocal centimeter (cm ).
High resolution mass spectra (HRMS) obtained by the direct analysis in real time (DART)
method were recorded on a Thermo Scientific Exactive Plus Orbitrap (Thermo Fisher
Scientific, Inc., Waltham, MA, USA).
3.2. Synthesis of IBA Analogues
3
.2.1. General Procedure for the Synthesis of IBAs 2a–v and 4
To a solution of 2-IBs (1.0 mmol) in MeCN (5 mL) was added Oxone® (738 mg,
1
.2 mmol) and H O (TW for Figure 3; Figure 4, Scheme 1 or DW for Scheme 2; Scheme 3
,
2
5
mL). After the mixture was stirred at room temperature for the appropriate time (see
Figure 4 and Scheme 1), the product was filtered under reduced pressure. The residue
was washed with water and acetone to obtain the corresponding IBAs 2a
Supplementary Materials for H NMR spectroscopic data) as a white powder.
–
v
and
4
(see
1

Molecules 2021, 26, 1897
8 of 18
3
3
.2.2. 1-Hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2a)
1H NMR (400 MHz, DMSO-d6):
7.72 (1H, td, J = 7.3, 0.9 Hz, H5), 7.86 (1H, d,
J = 8.2 Hz, H3), 7.97 (1H, ddd, J = 8.7, 7.4, 1.8 Hz, H4), 8.03 (1H, dd, J = 7.8, 1.4 Hz, H6), 8.08
1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
120.3 (C2), 126.2 (C3), 130.3 (C5), 131.0 (C1),
31.4 (C6), 134.4 (C4), 167.7 (COOH) ppm. IR (ATR, KBr): 2936 (OH), 1616 (C=O), 1566
C=O) cm . Mp: 243–244 C. H and C NMR data are consistent with those reported in
the literature [33].
δ
(
δ
1
(
ν
−
1
◦
1
13
3
3
.2.3. 5-Fluoro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2b)
1
H NMR (500 MHz, DMSO-d6):
δ
7.76 (1H, dd, J = 8.3, 2.6 Hz), 7.79–7.88 (2H, m),
114.2, 117.3 (d, J = 22.7 Hz), 121.7
8
.21 (1H, s) ppm. 13C NMR (125 MHz, DMSO-d6):
δ
(
d, J = 23.8 Hz), 128.3 (d, J = 8.4 Hz), 134.1 (d, J = 7.2 Hz), 163.9 (d, J = 246.8 Hz), 166.4 (d,
19
J = 2.4 Hz) ppm. F NMR (470 MHz, DMSO-d6): δ −116.2 (dt, J = 5.7, 8.6 Hz) ppm. IR
− ◦
1
1
13
(ATR, KBr): ν 2904 (OH), 1635 (C=O), 1577 (C=O) cm . Mp: 241–242 C. H and C NMR
data are consistent with those reported in the literature [104].
3
3
.2.4. 5-Chloro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2c)
1
H NMR (400 MHz, DMSO-d6):
δ
7.81 (1H, d, J = 8.7 Hz), 7.95 (1H, d, J = 2.3 Hz), 8.03
118.6, 128.1,
2905 (OH), 1624 (C=O), 1560 (C=O)
(
1
1H, dd, J = 8.7, 2.3 Hz), 8.28 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
30.3, 133.5, 134.0, 135.8, 166.3 ppm. IR (ATR, KBr):
δ
ν
−
1
◦
1
13
cm . Mp: 294–295 C. H and C NMR data are consistent with those reported in the
literature [105].
3
3
.2.5. 5-Bromo-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2d)
1
H NMR (400 MHz, DMSO-d6):
δ
7.74 (1H, d, J = 8.7 Hz), 8.07 (1H, d, J = 2.3 Hz), 8.15
119.5, 124.2,
2884 (OH), 1617 (C=O), 1557 (C=O)
(
1
1H, dd, J = 8.7, 2.3 Hz), 8.27 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
28.3, 133.3, 133.7, 136.8, 166.2 ppm. IR (ATR, KBr):
δ
ν
−
1
◦
1
13
cm . Mp: 236–238 C. H and C NMR data are consistent with those reported in the
literature [106].
3
3
.2.6. 1-Hydroxy-5-methyl-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2e)
1
H NMR (400 MHz, DMSO-d6):
δ
2.48 (3H, s), 7.70 (1H, d, J = 8.2 Hz), 7.79 (1H, dd,
20.1, 116.7,
3054 (OH), 1622 (C=O), 1569
C=O) cm . Mp: 212–214 C. H and C NMR data are consistent with those reported in
the literature [105].
J = 8.7, 1.8 Hz), 7.85 (1H, s), 8.01 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
25.9, 131.3, 131.4, 135.2, 140.4, 167.7 ppm. IR (ATR, KBr):
δ
1
(
ν
−
1
◦
1
13
3
3
.2.7. 1-Hydroxy-5-methoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2f)
1
H NMR (400 MHz, DMSO-d6):
J = 8.7, 2.8 Hz), 7.67 (1H, d, J = 9.2 Hz), 8.04 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
55.8, 108.9, 114.8, 121.5, 127.0, 132.9, 161.4, 167.4 ppm. IR (ATR, KBr): 2953 (OH), 1620
C=O), 1577 (C=O) cm . Mp: 217–218 C. H and C NMR data are consistent with those
reported in the literature [105].
δ 3.89 (3H, s), 7.52 (1H, d, J = 2.7 Hz), 7.55 (1H, dd,
δ
ν
−
1
◦
1
13
(
3
3
.2.8. 1-Hydroxy-3-oxo-1,3-dihydro-1λ -benzo[d][1,2]iodaoxol-5-yl acetate (2g)
1
H NMR (500 MHz, DMSO-d6):
d, J = 2.3 Hz), 7.84 (1H, d, J = 8.6 Hz), 8.16 (1H, s) ppm. 13C NMR (125 MHz, DMSO-d6):
0.8, 116.1, 124.2, 127.4, 127.9, 133.0, 152.5, 166.8, 169.0 ppm. IR (ATR, KBr): 2891 (OH),
δ 2.33 (3H, s), 7.74 (1H, dd, J = 8.6, 2.3 Hz), 7.77 (1H,
δ
2
ν
−
1
◦
1
759 (C=O), 1604 (C=O), 1559 (C=O) cm . Mp: 207–208 C. HRMS (DART, m/z) calcd for
+
C H IO [M + H] : 322.9411; found: 322.9413.
9
8
5

Molecules 2021, 26, 1897
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3
3
.2.9. 1-Hydroxy-5-(trifluoromethyl)-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2h)
1
H NMR (500 MHz, DMSO-d6):
δ
8.08 (1H, d, J = 8.0 Hz), 8.21 (1H, s), 8.33 (1H, d,
123.4 (q, J = 271.0 Hz),
25.5, 127.1 (d, J = 3.6 Hz), 127.9, 130.6 (d, J = 2.4 Hz), 131.6 (q, J = 32.6 Hz), 132.9, 166.3 ppm
J = 8.1 Hz), 8.38 (1H, s) ppm. 13C NMR (125 MHz, DMSO-d6):
δ
1
.
1
9
F NMR (470 MHz, DMSO-d6): δ −64.5 ppm. IR (ATR, KBr):
ν
2854 (OH), 1597 (C=O),
−
1
◦
+
1
559 (C=O) cm . Mp: 233–235 C. HRMS (DART, m/z) calcd for C H F IO [M + H] :
8
5
3
3
332.9230; found: 332.9227.
3
3
.2.10. 1-Hydroxy-5-nitro-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2i)
1
H NMR (400 MHz, DMSO-d6):
δ
8.10 (1H, d, J = 8.7 Hz), 8.54 (1H, s), 8.57 (1H, d,
124.8,
2834 (OH), 1617 (C=O), 1572
C=O), 1541 (C=O) cm . Mp: 214–216 C. H and C NMR data are consistent with those
reported in the literature [107].
J = 2.3 Hz), 8.73 (1H, dd, J = 8.7, 2.8 Hz) ppm. 13C NMR (100 MHz, DMSO-d6):
27.7, 128.1, 128.2, 133.4, 149.7, 165.9 ppm. IR (ATR, KBr):
δ
1
(
ν
−
1
◦
1
13
3
3
.2.11. 1-Hydroxy-3-oxo-1,3-dihydro-1λ -benzo[d][1,2]iodaoxole-5-carbonitrile (2j)
1H NMR (500 MHz, DMSO-d6): 8.01 (1H, d, J = 8.6 Hz), 8.32–8.41 (3H, m) ppm. 13
NMR (125 MHz, DMSO-d6): 113.5, 117.3, 126.4, 127.7, 132.9, 134.2, 137.0, 166.0 ppm. IR
δ
C
δ
−
1
◦
(ATR, KBr):
ν
2903 (OH), 1625 (C=O), 1582 (C=O), 1561 (C=O) cm . Mp: 234–236 C.
+
HRMS (DART, m/z) calcd for C H INO [M + H] : 289.9309; found: 289.9310.
8
5
3
3
3
.2.12. 1,5-Dihydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2k)
1
H NMR (400 MHz, DMSO-d6):
δ
7.36 (1H, dd, J = 8.7, 2.7 Hz), 7.40 (1H, d, J = 2.3 Hz),
106.6, 117.1,
7
.57 (1H, d, J = 9.2 Hz), 7.94 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
δ
1
22.0, 127.0, 132.8, 159.7, 167.6 ppm. IR (ATR, KBr):
ν
3447 (OH), 3234 (OH), 1576 (C=O)
−
1
◦
+
cm . Mp: 230–232 C. HRMS (DART, m/z) calcd for C H IO [M + H] : 280.9305; found:
7
6
4
280.9304.
3
3
.2.13. 6-Fluoro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2l)
1
H NMR (500 MHz, DMSO-d6):
δ
7.53–7.60 (2H, m), 8.01 (1H, dd, J = 8.0, 5.2 Hz), 8.21
113.5 (d, J = 27.4 Hz), 118.0 (d, J = 22.7 Hz),
(
1
(
(
1H, s) ppm. 13C NMR (125 MHz, DMSO-d6):
22.8 (d, J = 8.4 Hz), 128.3, 132.9 (d, J = 8.4 Hz), 166.0 (d, J = 254.0 Hz), 166.7 ppm. F NMR
470 MHz, DMSO-d6): δ −109.0 (dt, J = 5.8, 8.6 Hz) ppm. IR (ATR, KBr): 3091 (OH), 1636
C=O), 1586 (C=O) cm . Mp: 206–208 C. H and C NMR data are consistent with those
δ
1
9
ν
−
1
◦
1
13
reported in the literature [105].
3
3
7
.2.14. 6-Chloro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2m)
1
H NMR (400 MHz, DMSO-d6):
δ
7.75 (1H, d, J = 1.8 Hz), 7.78 (1H, dd, J = 7.8, 1.8 Hz),
122.1, 125.7,
2854 (OH), 1607 (C=O), 1557 (C=O)
.96 (1H, d, J = 8.2, 2.3 Hz), 8.27 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
30.6, 130.7, 132.2, 139.3, 166.7 ppm. IR (ATR, KBr):
δ
1
ν
−
1
◦
1
cm . Mp: 212–214 C. H NMR data is consistent with those reported in the literature [94].
3
3
.2.15. 6-Bromo-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2n)
1H NMR (500 MHz, DMSO-d6):
δ
7.80–7.98 (3H, m), 8.23 (1H, s) ppm. 13C NMR
(
2
125 MHz, DMSO-d6): 122.1, 127.9, 128.5, 131.0, 132.5, 133.5, 166.8 ppm. IR (ATR, KBr): ν
δ
−
1
◦
844 (OH), 1602 (C=O), 1556 (C=O) cm . Mp: 222–224 C. HRMS (DART, m/z) calcd for
+
C H BrIO [M + H] : 342.8461; found: 342.8460.
7
5
3
3
3
.2.16. 1-Hydroxy-6-(trifluoromethyl)-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2o)
1
H NMR (400 MHz, DMSO-d6):
δ
8.06 (1H, s), 8.10 (1H, d, J = 8.1 Hz), 8.20 (1H, d,
121.7, 123.1 (d, J = 3.6 Hz),
J = 8.0 Hz), 8.38 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
23.4 (d, J = 270.7 Hz), 127.6 (d, J = 3.6 Hz), 131.9, 133.9 (q, J = 32.2 Hz), 135.4, 166.4 ppm.
δ
1
9
1
F
NMR (370 MHz, DMSO-d6): δ −64.6 ppm. IR (ATR, KBr):
ν 2871 (OH), 1616 (C=O), 1560

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C=O) cm 1. Mp: 216–217 C. H and 13C NMR data are consistent with those reported in
−
◦
1
(
the literature [12].
3
3
.2.17. 1-Hydroxy-3-oxo-1,3-dihydro-1λ -benzo[d][1,2]iodaoxole-6-carboxylic acid (2p)
1H NMR (500 MHz, DMSO-d6):
δ
ppm. 13C NMR (125 MHz, DMSO-d6):
δ
ppm. IR
−
1
◦
(
ATR, KBr):
ν
2832 (OH), 1704 (C=O), 1616 (C=O), 1558 (C=O) cm . Mp: 291–293 C.
+
HRMS (DART, m/z) calcd for C H IO [M + H] : 308.9254; found: 308.9252.
8
6
5
3
3
.2.18. 5,6-Difluoro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2q)
1
H NMR (500 MHz, DMSO-d6):
δ
7.73 (1H, dd, J = 9.2, 6.9 Hz), 7.97 (1H, dd, J = 9.7,
115.5 (d, J = 22.7 Hz), 119.2 (d,
7
.4 Hz), 8.37 (1H, s) ppm. 13C NMR (125 MHz, DMSO-d6):
δ
J = 19.1 Hz), 129.16 (d, J = 2.4 Hz), 129.20 (d, J = 3.6 Hz), 151.3 (dd, J = 263.5, 13.1 Hz), 153.7
(
dd, J = 256.4, 14.3 Hz), 165.9 ppm. 19F NMR (470 MHz, DMSO-d6): δ −138.7–138.5 (m),
−
1
−
132.6–132.4 (m) ppm. IR (ATR, KBr):
ν
2895 (OH), 1624 (C=O), 1591 (C=O) cm . Mp:
◦
+
2
01–203 C. HRMS (DART, m/z) calcd for C H F IO [M + H] : 300.9168; found: 300.9170.
7
4
2
3
3
3
.2.19. 1-Hydroxy-5,6-dimethoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2r)
1H NMR (500 MHz, DMSO-d6): 3.89 (6H, s), 7.24 (1H, s), 7.46 (1H, s), 7.95 ppm. 13
NMR (125 MHz, DMSO-d6): 55.9, 56.0, 107.4, 110.7, 112.4, 123.9, 150.6, 154.1, 167.8 ppm.
IR (ATR, KBr): 3016 (OH), 1592 (C=O), 1559 (C=O) cm . Mp: 201–203 C. H and
δ
C
δ
−
1
◦
1
13
ν
C
NMR data are consistent with those reported in the literature [46].
3
3
.2.20. 7-Bromo-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2s)
1
H NMR (500 MHz, DMSO-d6):
δ
7.60 (1H, t, J = 7.7 Hz), 7.97 (1H, dd, J = 7.7,
119.6, 130.0,
1
1
1
.5 Hz), 8.02 (1H, dd, J = 7.5, 1.2 Hz) ppm. 13C NMR (125 MHz, DMSO-d6):
33.1, 135.4, 140.5, 146.1, 167.0 ppm. IR (ATR, KBr):
54–155 C. HRMS (DART, m/z) calcd for C H BrIO [M + H] : 342.8461; found: 342.8462.
δ
−
1
ν
3273 (OH), 1647 (C=O) cm . Mp:
◦
+
7
5
3
3
3
.2.21. 1-Hydroxy-7-methyl-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2t)
1
H NMR (400 MHz, DMSO-d6):
δ
2.79 (3H, s), 7.57–7.73 (2H, m), 7.90 (1H, d, J = 6.9 Hz
)
13
ppm. C NMR (100 MHz, DMSO-d6):
67.9 ppm. IR (ATR, KBr): 1672 (C=O) cm . Mp: 164–166 C. H NMR data are
δ
19.6, 128.7, 132.0, 132.6, 137.9, 139.1, 147.4,
−
1
◦
1
1
ν
consistent with those reported in the literature [106].
3
3
.2.22. 4-Fluoro-1-hydroxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2u)
1
H NMR (400 MHz, DMSO-d6):
δ
7.51 (1H, dd, J = 10.1, 8.2 Hz), 7.71 (1H, d, J = 7.7 Hz),
118.6
7
.90 (1H, td, J = 8.2, 4.6 Hz), 8.24 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
δ
(
1
d, J = 22.0 Hz), 119.2 (d, J = 11.5 Hz), 122.5 (d, J = 3.8 Hz), 123.2, 134.3 (d, J = 8.6 Hz),
19
63.8 (d, J = 4.8 Hz), 163.8 (d, J = 264.4 Hz) ppm. F NMR (375 MHz, DMSO-d6):
δ
−
114.7 (dd, J = 15.2, 4.9 Hz) ppm. IR (ATR, KBr): 3091 (OH), 1636 (C=O), 1586 (C=O)
cm . Mp: 213–214 C. H and C NMR data are consistent with those reported in the
literature [106,108].
ν
−
1
◦
1
13
3
3
.2.23. 1-Hydroxy-4-methyl-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (2v)
1
H NMR (400 MHz, DMSO-d6):
δ
2.70 (3H, s), 7.48–7.55 (1H, m), 7.72–7.80 (2H, m), 7.94
20.4, 122.2, 124.2, 128.2, 133.3, 133.4, 144.3,
(
1
1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
δ
− ◦
1
1
68.0 ppm. IR (ATR, KBr): ν 2926 (OH), 1625 (C=O), 1584 (C=O) cm . Mp: 212–213 C. H
and 13C NMR data are consistent with those reported in the literature [106].
3
3
.2.24. 1-Hydroxy-1λ -naphtho[2,3-d][1,2]iodaoxol-3(1H)-one (4)
1
H NMR (400 MHz, DMSO-d6):
δ
7.76 (2H, m), 8.14–8.33 (2H, m), 8.29 (1H, d,
115.9, 126.3,
3053 (OH),
J = 8.2 Hz), 8.39 (1H, s), 8.69 (1H, s) ppm. 13C NMR (100 MHz, DMSO-d6):
27.8, 127.9, 128.1, 128.9, 129.3, 131.7, 132.8, 135.8, 167.7 ppm. IR (ATR, KBr):
δ
1
ν

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698 (C=O), 1607 (C=O), 1559 (C=O) cm 1. Mp: 164–165 C. H and 13C NMR data are
−
◦
1
1
consistent with those reported in the literature [107].
3.3. Synthesis of Benziodoxole Alkoxides
3.3.1. General Procedure for the Synthesis of Benziodoxole Alkoxides (6)
To a suspension of IBA 2a (264 mg, 1.0 mmol) in an appropriate alcohol (10 mL) was
added MS3Å (1 g). After the mixture was stirred under the appropriate conditions (see
Figure 6), MS3Å was filtered using CH Cl , and the solvents were then removed by evap-
2
2
oration. The residue was washed with hexane and filtered to remove the corresponding
alcohol completely. The residue was dissolved with CH Cl and the extract was then
2
2
filtered through filter paper to remove unreacted substrate. Removal of the solvent by
evaporation gave the corresponding benziodoxole alkoxides 6a–h as a white powder.
3
3
.3.2. 1-Methoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6a)
1H NMR (500 MHz, CDCl3):
J = 8.1 Hz), 7.91 (1H, ddd, J = 8.6, 6.9, 1.2 Hz), 8.28 (1H, dd, J = 7.5, 1.2 Hz) ppm. C NMR
δ 4.29 (3H, s), 7.70 (1H, t, J = 7.7 Hz), 7.78 (1H, d,
1
3
(
ν
125 MHz, CDCl3):
δ
62.3, 118.6, 126.0, 130.6, 131.0, 132.9, 135.1, 168.0 ppm. IR (ATR, KBr):
−
1
◦
1
13
1653 (C=O) cm . Mp: 161–163 C. H and C NMR data are consistent with those
reported in the literature [28,109].
3
3
.3.3. 1-Ethoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6b)
1H NMR (500 MHz, CDCl3):
t, J = 7.4 Hz), 7.79 (1H, d, J = 8.9 Hz), 7.89 (1H, td, J = 8.6, 1.8 Hz), 8.28 (1H, dd, J = 7.2, 2.0
Hz) ppm. 13C NMR (125 MHz, CDCl3):
19.0, 69.9, 118.8, 125.9, 130.7, 131.0, 132.9, 135.0,
68.0 ppm. IR (ATR, KBr): 1655 (C=O) cm . Mp: 123–125 C. H and C NMR data are
δ 1.35 (3H, t, J = 6.9 Hz), 4.30 (2H, q, J = 6.9 Hz), 7.70 (1H,
δ
−
1
◦
1
13
1
ν
consistent with those reported in the literature [109].
3
3
.3.4. 1-(2,2,2-trifluoroethoxy)-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6c)
1H NMR (500 MHz, CDCl3):
δ 4.52 (2H, q, J = 8.6 Hz), 7.74 (1H, t, J = 7.5 Hz), 7.86
(
1H, d, J = 8.0 Hz), 7.97 (1H, ddd, J = 8.0, 6.9, 1.2 Hz), 8.27 (1H, dd, J = 7.5, 1.2 Hz) ppm.
13
C NMR (125 MHz, CDCl3):
δ 69.7 (q, J = 34.2 Hz), 119.0, 123.5 (q, J = 278.2 Hz), 126.5,
1
29.5, 131.4, 133.2, 135.9, 167.9 ppm. 19F NMR (470 MHz, CDCl ): δ −77.2 (q, J = 9.1 Hz)
3
−
1
◦
ppm. IR (ATR, KBr):
C H F IO [M + H] : 346.9386; found: 346.9384.
ν
1646 (C=O) cm . Mp: 139–141 C. HRMS (DART, m/z) calcd for
+
9
7
3
3
3
3
.3.5. 1-Propoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6d)
1H NMR (500 MHz, CDCl3):
1.02 (3H, t, J = 7.5 Hz), 1.72 (2H, sext, J = 7.1 Hz), 4.20
2H, t, J = 6.6 Hz), 7.70 (1H, t, J = 7.2 Hz), 7.79 (1H, d, J = 8.6 Hz), 7.89 (1H, t, J = 7.2 Hz),
.28 (1H, d, J = 7.5 Hz) ppm. 13C NMR (125 MHz, CDCl3):
10.1, 26.5, 76.0, 118.9, 125.9,
30.7, 130.9, 132.8, 135.0, 167.9 ppm. IR (ATR, KBr): 1651 (C=O) cm . Mp: 146–148 C.
HRMS (DART, m/z) calcd for C H IO [M + H] : 306.9826; found: 306.9823.
δ
(
8
1
δ
−
1
◦
ν
+
10
12
3
3
3
.3.6. 1-Isopropoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6e)
1H NMR (500 MHz, CDCl3):
1.36 (6H, d, J = 6.3 Hz), 4.33 (1H, sep, J = 6.1 Hz), 7.69
1H, t, J = 7.4 Hz), 7.82 (1H, d, J = 7.5 Hz), 7.88 (1H, td, J = 7.8, 1.5 Hz), 8.28 (1H, dd, J = 7.5
δ
(
1
1
,
.7 Hz) ppm. 13C NMR (125 MHz, CDCl3):
34.8, 168.0 ppm. IR (ATR, KBr): 1653 (C=O) cm . Mp: 253–254 C. H and C NMR
δ 25.2, 75.6, 119.1, 126.0, 130.8, 130.9, 132.7,
−
1
◦
1
13
ν
data are consistent with those reported in the literature [109].
3
.3.7. 1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1 3
λ -benzo[d][1,2]iodaoxol-3(1H)-one (6f)
1H NMR (500 MHz, CDCl3):
δ
4.80 (1H, sep, J = 5.8 Hz), 7.74 (1H, ddd, J = 8.0, 7.5, 1.4
Hz), 7.97–8.04 (2H, m), 8.24 (1H, dd, J = 7.4, 1.2 Hz) ppm. 1 C NMR (125 MHz, CDCl3):
3
δ
76.1 (quin, J = 32.5 Hz), 119.4, 122.2 (q, J = 283.8 Hz), 127.3, 128.5, 131.6, 133.3, 136.4,

Molecules 2021, 26, 1897
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1
1
4
68.1 ppm. 19F NMR (470 MHz, CDCl ): δ −76.0 (d, J = 5.7 Hz) ppm. IR (ATR, KBr):
ν
3
−
1
◦
+
661 (C=O) cm . Mp: 148–149 C. HRMS (DART, m/z) calcd for C H F IO [M + H] :
10
6
6
3
14.9260; found: 414.9258.
3
3
.3.8. 1-Butoxy-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6g)
1H NMR (500 MHz, CDCl3):
δ 0.98 (3H, t, J = 7.5 Hz), 1.46 (2H, sext, J = 7.4 Hz), 1.68
(
2H, quin, J = 7.2 Hz), 4.24 (2H, t, J = 6.6 Hz), 7.70 (1H, t, J = 7.5 Hz), 7.78 (1H, d, J = 8.0
13
Hz), 7.89 (1H, t, J = 7.5 Hz), 8.28 (1H, d, J = 7.5 Hz) ppm. C NMR (125 MHz, CDCl3):
3.9, 19.0, 35.4, 74.2, 118.9, 125.9, 130.7, 131.0, 132.9, 135.0, 167.9 ppm. IR (ATR, KBr): 1650
C=O) cm . Mp: 143–144 C. H and C NMR data are consistent with those reported in
the literature [110].
δ
1
(
ν
−
1
◦
1
13
3
3
.3.9. 1-(tert-Butoxy)-1λ -benzo[d][1,2]iodaoxol-3(1H)-one (6h)
1H NMR (500 MHz, CDCl3):
1.41 (9H, s), 7.67 (1H, ddd, J = 8.1, 7.5, 1.8 Hz), 7.83–7.91
2H,m), 8.26 (1H, dd, J = 8.1, 1.8 Hz) ppm. 13C NMR (125 MHz, CDCl3):
30.4, 78.6, 119.6,
δ
(
1
2
δ
−
1
26.2, 130.8, 131.0, 132.4, 134.7, 168.0 ppm. IR (ATR, KBr):
65 C. HRMS (DART, m/z) calcd for C H IO [M + H] : 320.9982; found: 320.9980.
ν
1659 (C=O) cm . Decomp:
◦
+
11
13
3
3
.4. Synthesis of Benziodoxole Acetates
.4.1. General Procedure for the Synthesis of Benziodoxole Acetates (7)
MS3Å (0.5 g) was added to a suspension of IBAs 2a (0.50 mmol) in AcOH (5 mL),
and the mixture was stirred under the appropriate conditions (see Scheme 4). Then, MS3Å
was filtered using CH Cl , and the solvents were removed by evaporation. The residue
3
–
i
2
2
was washed with ether and filtered to remove AcOH completely. The resulting residue
was dissolved with CH Cl , and the extract was then filtered through filter paper to
2
2
remove unreacted substrate. After solvent removal by evaporation, the corresponding
benziodoxole acetates 7a–i were obtained as a white powder.
3
3
.4.2. 3-Oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7a)
1H NMR (500 MHz, CDCl3):
J = 8.6, 6.9, 1.2 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.25 (1H, dd, J = 7.5, 1.2 Hz) ppm. C NMR
125 MHz, CDCl3): 20.2, 118.3, 128.9, 129.2, 131.2, 133.1, 136.1, 168.1, 176.3 ppm. IR (ATR,
KBr): 1684 (C=O) cm . Mp: 220–222 C. H and C NMR data are consistent with those
δ 2.27 (3H, s), 7.72 (1H, td, J = 7.5, 1.2 Hz), 7.94 (1H, ddd,
1
3
(
δ
−
1
◦
1
13
ν
reported in the literature [109].
3
3
.4.3. 5-Fluoro-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7b)
1
H NMR (500 MHz, CDCl ):
δ
2.26 (3H, s), 7.64 (1H, ddd, J = 8.6, 7.7, 2.9 Hz), 7.94–8.00
20.2, 111.3, 120.0 (d, J = 23.8 Hz), 123.7 (d,
J = 22.7 Hz), 131.0 (d, J = 8.3 Hz), 131.8 (d, J = 7.2 Hz), 165.0 (d, J = 252.8 Hz), 166.8, 176.4
3
(
2H, m) ppm. 13C NMR (125 MHz, CDCl3):
δ
19
ppm. F NMR (470 MHz, CDCl ): δ −110.8 (td, J = 7.2, 4.3 Hz) ppm. IR (ATR, KBr):
ν 1696
3
−
◦
1
13
(
C=O) cm 1. Mp: 225–226 C. H and C NMR data are consistent with those reported in
the literature [111].
3
3
.4.4. 5-Chloro-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7c)
1H NMR (500 MHz, CDCl3):
2.27 (3H, s), 7.87 (1H, dd, J = 8.6, 2.3 Hz), 7.93 (1H,
d, J = 9.2 Hz), 8.22 (1H, d, J = 1.7 Hz) ppm. 13C NMR (125 MHz, CDCl3):
20.2, 115.5,
δ
δ
−
1
1
2
30.4, 130.9, 133.0, 136.0, 138.8, 166.7, 176.4 ppm. IR (ATR, KBr): ν 1698 (C=O) cm . Mp:
44–245 C. H and C NMR data are consistent with those reported in the literature [105].
◦
1
13
3
3
2
.4.5. 5-Bromo-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7d)
1H NMR (500 MHz, CDCl3):
δ
2.27 (3H, s), 7.85 (1H, d, J = 9.2 Hz), 8.01 (1H, dd, J = 8.6
,
.3 Hz), 8.37 (1H, d, J = 1.8 Hz) ppm. 13C NMR (125 MHz, CDCl3):
δ
20.2, 116.5, 126.6, 130.7,

Molecules 2021, 26, 1897
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1680 (C=O) cm 1. Mp: 226–228 C
−
◦
.
1
31.0, 136.1, 138.9, 166.6, 176.4 ppm. IR (ATR, KBr):
ν
1
13
H and C NMR data are consistent with those reported in the literature [112].
3
3
.4.6. 5-Methyl-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7e)
1H NMR (500 MHz, CDCl3):
.84 (1H, d, J = 8.6 Hz), 8.07 (1H, d, J = 1.8 Hz) ppm. 13C NMR (125 MHz, CDCl3):
0.8, 114.6, 128.9, 133.6, 137.1, 142.3, 168.3, 176.4 ppm. IR (ATR, KBr): 1682 (C=O), 1659
δ
2.25 (3H, s), 2.56 (3H, s), 7.73 (1H, dd, J = 8.6, 1.7 Hz),
20.3,
7
2
(
δ
ν
−
1
◦
1
13
C=O) cm . Mp: 215–217 C. H and C NMR data are consistent with those reported in
the literature [105].
3
3
.4.7. 5-Methoxy-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7f)
1H NMR (500 MHz, CDCl3):
2.25 (3H, s), 3.94 (3H, s), 7.46 (1H, dd, J = 9.2, 2.9 Hz),
.74 (1H, d, J = 2.9 Hz), 7.81 (1H, d, J = 8.6 Hz) ppm. 13C NMR (125 MHz, CDCl3):
20.3,
6.2, 106.8, 115.9, 124.5, 129.7, 130.6, 162.7, 168.1, 176.4 ppm. IR (ATR, KBr): 1697 (C=O),
δ
7
5
1
δ
ν
− ◦
1
1
13
681 (C=O), 1656 (C=O) cm . Mp: 207–209 C. H and C NMR data are consistent with
those reported in the literature [105].
3
3
.4.8. 3-Oxo-1λ -benzo[d][1,2]iodaoxole-1,5(3H)-diyl diacetate (7g)
1
H NMR (500 MHz, CDCl ):
δ
2.26 (3H, s), 2.37 (3H, s), 7.68 (1H, dd, J = 8.9, 2.6 Hz),
20.3, 21.1, 113.6, 126.2, 129.8, 130.3,
3
7
1
.96–8.02 (2H, m) ppm. 13C NMR (125 MHz, CDCl3):
30.9, 153.6, 167.2, 168.7, 176.5 ppm. IR (ATR, KBr):
HRMS (DART, m/z) calcd for C H IO [M + H] : 364.9517; found: 364.9518.
δ
−
1
◦
ν
1690 (C=O) cm . Mp: 153–154 C.
+
11
10
6
3
3
.4.9. 3-Oxo-5-(trifluoromethyl)-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7h)
1H NMR (500 MHz, CDCl3):
2.29 (3H, s), 8.14 (1H, dd, J = 8.6, 1.7 Hz), 8.20 (1H, d,
J = 8.6 Hz), 8.52 (1H, d, J = 1.7 Hz) ppm. 13C NMR (125 MHz, CDCl3):
20.2, 121.9, 122.8
q, J = 271.4 Hz), 130.1 (d, J = 3.6 Hz), 130.4 (d, J = 9.5 Hz), 132.4 (d, J = 2.4 Hz), 134.5 (q,
δ
δ
(
19
J = 33.8 Hz), 166.7, 176.5 ppm. F NMR (470 MHz, CDCl ): δ −64.9 ppm. IR (ATR, KBr):
ν
3
−
1
◦
1
[
692 (C=O), 1647 (C=O) cm . Mp: 212–213 C. HRMS (DART, m/z) calcd for C H F IO
1
0
7
3
4
+
M + H] : 374.9336; found: 374.9334.
3
3
2
1
2
.4.10. 5-Nitro-3-oxo-1λ -benzo[d][1,2]iodaoxol-1(3H)-yl acetate (7i)
1H NMR (500 MHz, CDCl3):
.5 Hz), 9.04 (1H, d, J = 2.3 Hz) ppm. 13C NMR (125 MHz, CDCl3):
31.0, 131.5,150.8, 165.7, 176.6 ppm. IR (ATR, KBr): 1705 (C=O), 1665 (C=O) cm . Mp:
δ
2.30 (3H, s), 8.27 (1H, d, J = 9.2 Hz), 8.71 (1H, dd, J = 9.0
,
δ
20.2, 124.1, 127.6, 129.8,
−
1
ν
◦
1
13
09–210 C. H and C NMR data are consistent with those reported in the literature [107].
4. Conclusions
We have presented a practical synthetic method for IBA from 2-IB without contamina-
®
tion by hazardous pentavalent IBX using cost-effective Oxone in aqueous solution. This
highly safe, convenient method operates under mild conditions such as room temperature,
which contrasts with traditional method using reflux conditions and expensive NaIO in
4
AcOH solution. The use of mild conditions circumvents the problem of the formation of
byproducts such as potentially explosive pentavalent cyclic hypervalent iodine compound,
i.e., IBX; the contamination of IBX into IBA is generally not desired for safety reasons.
The reaction time can be shortened by heating; in this case, addition of a ferric salt in our
reaction system can effectively suppress the formation of IBX as byproducts. In addition, a
convenient derivatization of the hydroxy group of IBAs by solvolytic treatment is presented.
◦
These derivatizations were generally achieved under mild conditions below 80 C. Our
methods, which do not require any chromatography technique, can be performed safely
and would be suitable for large-scale synthesis.
1
Supplementary Materials: Supplementary materials are available online, H NMR spectroscopic
data for the compounds 2a–v and 4.

Molecules 2021, 26, 1897
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Author Contributions: H.C. found the selective reaction to obtain IBAs using Oxone® and the
solvolytic functionalization for IBA and drafted the manuscript; N.K., H.Y., and N.T. also contributed
to the experiments; T.D. directed this study as a project and finalized the manuscript with critical
discussion. All authors have read and agreed to the published version of the manuscript.
Funding: This work was financially supported by a Grant-in-Aid for Scientific Research (C) (JSPS
KAKENHI Grant Number JP19K05466) from JSPS and the Ritsumeikan Global Innovation Research
Organization (R-GIRO) project. H.C. also acknowledges support from a Grant-in-Aid for Early-Career
Scientists (JSPS KAKENHI Grant Number 20K15103) from JSPS.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in the communication.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.
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