Redetermination of the Structure of a Water-Soluble Hypervalent Iodine(V) Reagent AIBX and Its Synthetic Utility in the Oxidation of Alcohols and Synthesis of Isoxazoline N-Oxides

Article abstract of DOI:10.1021/acs.joc.9b02328

The structure of a water-soluble hypervalent iodine(V) reagent AIBX is re-examined through its single-crystal X-ray analysis and theoretical calculations including Mayer bond order and localized orbital locator (LOL) and AIBX is believed to be a pseudocyclic iodylarene because of the strong electron-withdrawing nature of the trimethylammonium cation on its phenyl ring, which would decrease the electron density of carboxylic anion and make the ortho-carboxyl oxygen anion incapable to form hypervalent bond with iodine atom. However, the cyclic benziodoxole structure of AIBX could be obtained by adding a Br?nsted acid, which was supported by the calculation result including the increase of Mayer bond order and the shortening of the I-O bond length. Moreover, the fact that the system of AIBX and TFA could oxidize various alcohols to their corresponding carbonyl compounds would indicate that AIBX constitutes a cyclic benziodoxole structure under acidic conditions. In addition, an efficient method has been developed for the synthesis of isoxazoline N-oxides via AIBX-induced dehydrogenative cyclization using β-keto esters as substrates and methyl nitroacetate as a nucleophile.

Full text of DOI:10.1021/acs.joc.9b02328

Subscriber access provided by WESTERN SYDNEY U
Featured Article
Re-determination of the Structure of a Water-Soluble Hypervalent
Iodine(V) Reagent AIBX and Its Synthetic Utility in the
Oxidation of Alcohols and Synthesis of Isoxazoline N-Oxides
Hui-Jie Shen, Ya-Nan Duan, Ke Zheng, and Chi Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02328 • Publication Date (Web): 30 Oct 2019
Downloaded from pubs.acs.org on November 3, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
The Journal of Organic Chemistry
Re-determination of the Structure of a Water-Soluble Hypervalent
Iodine(V) Reagent AIBX and Its Synthetic Utility in the Oxidation of
Alcohols and Synthesis of Isoxazoline N-Oxides
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hui-Jie Shen, Ya-Nan Duan, Ke Zheng, and Chi Zhang*
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
O
I
O
I
O
O
O
O
HO
O
+ H
- H
N
N
AIBX
cyclic AIBX
O2N
CO2Me
O
O
O
AIBX (2.5 equiv)
+
R''
O
CH3COOH (1.0 equiv)
R'
AIBX (1.5 equiv)
TFA (1.5 equiv)
O
N
O
OH
R2
O
CH3CN/H2O (1/3, v/v)
0°C - rt
R'
H
R2
R1
R1
HFIP, rt
R''
MeO2C
2
3
4
5
R'' = OEt, OBut, OBn,
Me, Et, NHMe, NH2
ABSTRACT: The structure of a water-soluble hypervalent iodine(V) reagent AIBX is re-examined through its single crystal
X-ray analysis and theoretical calculation including Mayer bond order and localized orbital locator (LOL), and AIBX is
believed to be a pseudocyclic iodylarene because of the strong electron-withdrawing nature of the trimethylammonium
cation on its phenyl ring, which would decrease the electron density of carboxylic anion and make ortho-carboxyl oxygen
anion incapable to form hypervalent bond with iodine atom. However, the cyclic benziodoxole structure of AIBX could be
obtained by adding a Brønsted acid, which was supported by the calculation result including the increase of Mayer bond
order and the shortening of I-O bond length. Moreover, the fact that the system of AIBX and TFA could oxidize various
alcohols to their corresponding carbonyl compounds would indicate that AIBX constitute to be a cyclic benziodoxole
structure under acidic conditions. In addition, an efficient method has been developed for the synthesis of isoxazoline N-
oxides via AIBX-induced dehydrogenative cyclization using β-keto esters as substrates and methyl nitroacetate as a
nucleophile.
Introduction
IBX is a commonly used hypervalent iodine(V) reagent owing to its rich reactivities including the efficient oxidation of
alcohols.1 It is worth noting that IBX has poor solubility in water. To improve the water-solubility of IBX, a hypervalent
iodine(V) reagent called AIBX having trimethylammonium group on the phenyl ring was designed and synthesized by our
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
group in 2011,2a and we believed that AIBX was an IBX’s derivative with a five-membered heterocyclic benziodoxole
structure initially (Figure 1, 1A), not to be pseudocyclic iodylarene (Figure 1, 1B), and then we focused on the exploration of
the reactivity of AIBX. Since the first reactivity of AIBX-mediated dehydrogenation of various six-membered β-keto esters
was found, our group has reported methods of using AIBX-induced dehydrogenative α,β’-bifunctionalization of β-keto esters
to construct 2,3-dihydrofurans, cyclopropanes and epoxides so far.2b-f
1
2
3
4
5
6
7
8
9
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
I
OH
I
I
O
O
O
Me3N
Me3N
O
O
IBX
1A
1B
Figure 1. IBX and AIBX (heterocyclic benziodoxole 1A and pseudocyclic 1B)
Then, we tried the oxidation of alcohols by AIBX. The reaction was conducted with p-nitrobenzyl alcohol and AIBX in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at room temperature (Scheme 1a). To our surprise, it was found that the oxidation
of p-nitrobenzyl alcohol by AIBX did not happen. However, when trifluoroacetic acid (TFA) was added into the system, the
reaction did oxidize p-nitrobenzyl alcohol to its corresponding aldehyde in a quantitative yield (Scheme 1b). Notably, it is
generally known that IBX can efficiently oxidize various alcohols to their corresponding carbonyl compounds.3 On the other
hand, noncyclic iodylarenes such as PhIO2 are not effective oxidants toward alcohols without acid additives.4 Because of the
oxidative reactivity of AIBX in alcohol oxidation is identical to PhIO2 rather than IBX having a five-membered heterocyclic
benziodoxole structure,4e we speculated that AIBX would adopt a pseudocyclic structure 1B.
Scheme 1. The Oxidation of p-Nitrobenzyl Alcohol by AIBX
O
OH
AIBX (1.5 equiv)
(a)
HFIP
rt, 24 h
O2N
no reaction
O2N
0.2 mmol
30.6 mg
recovery yield of p-nitrobenzyl alcohol: 98%
O
OH
AIBX (1.5 equiv)
TFA (1.5 equiv)
(b)
HFIP
rt, 6 h
O2N
quantitative yield
O2N
0.2 mmol
30.6 mg
In general, IBX and its analogs with a bond distance between the iodine(V) atom and the ortho-carboxyl oxygen atom in the
range of 2.00-2.48 Å can be classified as cyclic benziodoxole iodylarenes (Figure 2a) , such as IBX,5a mIBX,5b Me-IBX5c and
FIBX;5d while iodylarenes with the intramolecular I···O bond distance longer than 2.50 Å are considered to be pseudocyclic
iodylarenes6 (Figure 2b), such as IBX-amides,4b IBX-esters4c and IBX-SO3K.4e Therefore, for AIBX, it is uncertain whether
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
AIBX is cyclic benziodoxole 1A or pseudocyclic iodylarenes 1B if only the intramolecular I···O bond distance of 2.498 Å,
1
2
which is a boundary value, is used as a criterion.
3
4
5
(a) Cyclic benziodoxole iodine(V) reagents with an ortho-carboxy group to the iodine
6
7
8
9
F
O
O
O
OH
O
OH
O
Me
OH
O
O
OH
O
F
F
I
I
I
I
MeO
O
O
O
CO2H
F
FIBX
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me-IBX
IBX
mIBX
(b) Pseudocyclic iodine(V) reagents with an ortho-carboxy group to the iodine
O
O
O
O
O
O
O
O
O
I
I
I
KO3S
NHR
IBX amides
OR
IBX esters
OH
IBX-SO3K
Figure 2. Five-Membered Heterocyclic and Pseudocyclic Iodine(V) Reagents
Results and Discussion
The intramolecular I(1)···O(1) distance is 2.498 Å shown in Figure 3, a critical value for determining whether AIBX is cyclic
benziodoxole iodylarenes 1A or not, which is longer than that in IBX (2.263 Å) but closer to that in IBX-SO3K (2.61 Å) which
is a pseudocyclic iodylarene. Therefore, we consider AIBX to be a pseudocyclic iodylarenes 1B. As shown in Figure 4a, for the
pseudocyclic iodylarenes,7 the difference of bond length between I-O(2) and I-O(3) varies in the range of 0.001-0.030 Å;
while it varies in the range of 0.036-0.141 Å for cyclic benziodoxole iodylarenes (Figure 4b). The difference between I-O (2)
and I-O (3) bond length in AIBX is 0.014 Å, indicating that AIBX belongs to pseudocyclic iodylarenes. Therefore, it is more
likely that AIBX is present as pseudocyclic iodylarene 1B.
Figure 3. Perspective Drawing of AIBX with 50% Ellipsoid Probability
(a) Pseudocyclic iodylarenes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
3
O
2
3
3
3
O
O
O
O
2
2
2
O
O
O
I
1
I
I
I
1
2
1
O
1
O
1
O
N
O
OR
3
RO
NHR
4
5
6
7
1C
R = nBu R = iPr
1D
1E
1F
R = Me R = iPr R = (S)-CH(Bn)CO2Me
[a]
dI-O1 (Å)
dI-O2 (Å)
dI-O3 (Å)
2.931
1.793
1.792
2.882
1.806
1.803
2.697
1.794
1.806
2.818
1.817
1.803
2.571
1.807
1.823
2.682 2.767
1.787 1.813
1.805 1.817
8
d = | dI-O2 - dI-O3 | (Å) 0.001
0.003
0.012
0.014
0.016
0.018 0.004
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
2
O
O
2
2
O
O
2
3
O
3
3
O
O
I
O
I
I
I
1
1
1
O
S
O
O
PPh2
O
1
But
O
S
O
NHR
OH
KO3S
IBX-SO3K
1I
1G
1H
R = (S)-CH(iPr)CO2Me
[a]
dI-O1 (Å)
dI-O2 (Å)
dI-O3 (Å)
2.781 2.858
1.795 1.809
1.820 1.820
2.693
1.822
1.796
2.603
1.818
1.789
2.61
1.80
1.83
0.025 0.011
0.026
0.029
0.03
d = | dI-O2 - dI-O3 | (Å)
(b) Cyclic benziodoxole iodylarenes
2
O
2
OH
3
3
O
O
I
I
1
1
O
O
N
Bu
Me
O
IBX
1J
[a]
2.466
1.745
1.836
2.366
1.771
1.807
2.263
1.925
1.784
dI-O1 (Å)
dI-O2 (Å)
dI-O3 (Å)
d = | dI-O2 - dI-O3 | (Å)
0.036 0.091
0.141
[a] Data for two independent molecules in crystal unit cell.
Figure 4. I-O Bond Lengths and the Difference between I-O(2) and I-O(3) Bond Length in Pseudocyclic and Cyclic
Benziodoxole Iodylarenes
To further determine the structure of AIBX, we started computational studies based on the X-ray structure of AIBX at the
DFT M06-2X/[6-31+G(d) + Lanl2dz(I)] level of theory, especially Mayer bond order (MBO) and localized orbital locator
(LOL).
Mayer bond order (MBO)8 is established to inspect the electronic structures, and it is generally accepted that a lower value
of MBO implies a lower bond strength. The hypervalent three-center-four-electron (3c-4e) bond has a theoretical bond
order of 1.0, and the endocyclic I-O(1) bond in cyclic benziodoxole iodylarenes has a theoretical bond order of 0.5.9 As
shown in Figure 5, the endocyclic I-O(1) bond in IBX has an MBO value of 0.35, which is close to the theoretical bond order
of 0.5. While the endocyclic I···O(1) bond in AIBX has a MBO value of 0.13, much smaller than the theoretical bond order of
0.5, indicating that the probability of forming a hypervalent bond is very small
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
2
3
3O
O
2
O
OH
I
1
2
3
4
5
6
7
8
9
10
I
1
O
1
O
Me3N
O
O
AIBX
IBX
Mayer bond order
dI-O1 from crystals (Å)
0.35
0.13
2.263
2.498
Figure 5. I-O(1) Mayer Bond Orders and Their Bond Lengths in IBX and AIBX
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To observe characteristics of hypervalent iodine bond and localization of electron density of bonds, we calculated and
visualized localized orbital locator (LOL)10 of IBX and AIBX (Figure 6). The LOL values are visualized on a blue-green-red
color scale, in which blue and red colors indicate no electron and high electron localization respectively, and the green
region shows a certain degree of valence electron density between blue and red extremes. In IBX, the green color region
between I and O(1) indicated that there was a certain degree of valence electron density between I and O(1), which
participated in the formation of hypervalent iodine bond. However, in AIBX, there was a light blue color region between I
and O(1), indicating that the electron density between I and O(1) was very low and the intramolecular interaction was thus
weak. Consequently, it was most likely that a hypervalent bond was not formed between I and O(1) in AIBX and AIBX was
present as pseudocyclic iodylarene 1B, which was consistent with the MBO calculation result.
AIBX is believed to be a pseudocyclic iodylarene 1B through its single crystal X-ray analysis and theoretical calculation
including Mayer bond order and localized orbital locator (LOL). The reason for not forming a hypervalent bond between I
and O(1) in AIBX was that the trimethylammonium cation inductively withdraws electron density from the aromatic ring,
which would decrease the electron density of carboxylic anion and make ortho-carboxyl oxygen anion incapable to form
hypervalent bond with iodine(V) atom.
Further computational studies showed that when the oxygen atom of the IO2 in AIBX was protonated, the MBO of I-O(1)
increased from 0.13 to 0.36, and the bond length of I-O(1) was shortened from 2.498 Å to 2.07 Å, which were similar to
those of IBX, and this indicated that a cyclic benziodoxole structure of AIBX could be achieved by adding an external acid.
This was because the iodine(V) center was thus more electrophilic upon protonation to form hypervalent bond with the
ortho-carboxy oxygen atom. Thus, it was fully understood that the AIBX-TFA system in HFIP11 had an excellent alcohol
oxidation reactivity resulted from the cyclic benziodoxole structure of AIBX upon protonation (Scheme 1b).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
IBX
AIBX
Figure 6. Color-Filled Maps of Localized Orbital Locator for IBX and AIBX
A range of alcohols can be oxidized to their corresponding carbonyl compounds by the AIBX-TFA system (Scheme 2).
Aliphatic primary alcohol (hexadecan-1-ol 2a) and benzylic primary alcohols (2b-d) were readily oxidized to their
corresponding aldehydes 3a-d in excellent yields without overoxidation to the carboxylic acid. An allylic alcohol 2-methyl-
3-phenyl-2-propenol (2e) was found to undergo oxidation in an excellent yield of 94% without oxidizing the carbon-carbon
double bond. As for acyclic aliphatic secondary alcohol (2f), aromatic secondary alcohols (2g-h) and cyclic secondary
alcohols (4-tert-butylcyclohexanol 2i, testosterone 2j and dihydrocholesterol 2k), they were oxidized to their
corresponding ketones 3f-k in excellent yields. 1,2-Diphenylethane-1,2-diol (2l) could be oxidized to benzoin (3l) or benzil
(3m) in excellent yield without detection of benzaldehyde from oxidative cleavage of the glycolic C-C bond. It should be
noted that excess AIBX was employed to ensure complete conversion of alcohols with a satisfactory reaction rate (e.g., 2a,
2f, 2i and 2k). The oxidation of a fluorinated alcohol 1-phenyl-2,2,2-trifluoroethanol was also examined under the optimal
conditions, however, no reaction took place after 55 h.
Scheme 2. Substrate Scope of the Oxidation of Alcohols by AIBX-TFA System
ACS Paragon Plus Environment

Page 7 of 24
The Journal of Organic Chemistry
AIBX (1.5 equiv)
TFA (1.5 equiv)
OH
R2
O
1
2
R1
R2
R1
HFIP (2 mL), rt
3
2
, 0.2 mmol
3
4
5
6
7
8
O
O
O
O
O
Me
O
O
14
O2N
[a]
3b
3c
3d
3e
, 10 min, 94%
, 6 h, quantitative yield
, 18 min, 97%
, 10 min, 83%
O
3a
, 5 h, 87%
O
9
O
O
10
11
12
13
14
15
16
17
18
19
20
Br
[a]
[b]
3g
3h
, 10 min, quantitative yield
, 15 min, quantitative yield
3f
3i
, 12 h, 87%
, 1.7 h, 99%
O
3
O
OH
H
H
H
H
O
O
H
H
O
O
[c]
[d]
[e]
3j
, 20 min, 92%
3k
3l
3m
, 0.5 h, 94%
, 7 h, 95%
, 6 h, 85%
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[a] 2.0 equiv AIBX and 2.0 equiv TFA were used. [b] 1.8 equiv AIBX and 1.8 equiv TFA were used. [c] 2.5 equiv AIBX and 2.5
equiv TFA were used. [d] 1.1 equiv AIBX and 1.1 equiv TFA were used. [e] 2.2 equiv AIBX and 2.2 equiv TFA were used.
Furthermore, it was also in the presence of acid (AcOH) that AIBX could effectively facilitate the synthesis of isoxazoline N-
oxides using β-keto esters as substrates and methyl nitroacetate as a nucleophile (Scheme 3). Isoxazoline N-oxides are
useful heterocyclic structures,12 and several approaches to isoxazoline N-oxides have been developed, such as a tandem
nitroaldol-intramolecular cyclization of α-haloketones/α-haloaldehydes and epoxides,13 intramolecular oxidative N-O
coupling of β-hydroxy ketoximes,14 and [4+1] annulation of nitroalkenes and a carbon nucleophiles.15 To the best of our
knowledge, in the oxidative coupling reactions to synthesize isoxazoline N-oxides, other types of substrates have never been
reported except for β-hydroxy ketoximes.
Scheme 3. Synthesis of Isoxazoline N-Oxides Promoted by AIBX
and X-ray crystallography with 50% Ellipsoid Probability
O
CO2Et
O
(2 equiv)
COOMe
O2N
O
AIBX (2.5 equiv)
CH3COOH (1 equiv)
CO2Et
N
O
CH3CN/H2O, (1/3, v/v)
0°C - rt
MeO2C
5a
4a
, 0.2 mmol
We began our exploration by using starting material 4a with methyl nitroacetate (2.0 equiv) in the presence of 2.5 equiv of
AIBX in a solution of 1:3 (v/v) CH3CN/H2O at room temperature, which affording the product 5a in 56% yield within 6 h,
and the structure of 5a was confirmed by X-ray crystallography. The reaction was also tried with 1.2 equivalents of AIBX
and afforded only 45% yield of 5a after 32 h. Further investigation of reaction conditions revealed that a system of 2.0 equiv
of methyl nitroacetate, 2.5 equiv of AIBX, and 1.0 equiv of AcOH in 1:3 (v/v) CH3CN/ H2O at 0oC to room temperature was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
optimal (for details, see Table S1 of the supporting information. Notably, 2-iodoxybenzoic acid (IBX) was employed as the
oxidant under the otherwise identical reaction conditions, and the yield was only 3%. It showed the difference in the
chemical structure of IBX and AIBX. When other water-soluble hypervalent iodine reagents, such as mIBX, PIBS, IBX-SO3K,
PISA, HTIB and AIBA, were subjected to the standard reaction conditions, the results were disappointing).
1
2
3
4
5
6
7
8
9
We investigated the generality of the reaction by using various β-keto esters, β-diketones and β-keto amides as substrates
(Scheme 4). As expected, β-keto esters with electron-donating or -withdrawing groups on the phenyl ring smoothly gave
products in high yields (5b-k), which suggested that the electronic properties of the phenyl ring had little influence on the
outcome of the reaction. Substrates bearing tert-butyl and benzyl ester groups could also generate the corresponding
products 5l and 5m (84% and 72% yields, respectively). Substrates with a piperonyl moiety, a naphthalene ring and a
thiophene moiety, all of which are oxidizable, were compatible with the present reaction conditions, providing 5n, 5o and
5p (98%, 61% and 78% yields, respectively). Moreover, the reaction of β-diketones 4q and 4r proceeded smoothly to afford
the desired products 5q and 5r (71% and 61% yields, respectively). In addition, β-keto amides proved to be good
substrates for this transformation, and gave the corresponding products 5s and 5t in 98% and 62% yields, respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Substrate Scope of AIBX-Mediated Synthesis of Isoxazoline N-Oxides
O
O
R''
O
(2 equiv)
COOMe
O
O2N
R'
O
AIBX (2.5 equiv)
O
N
R'
CH3COOH (1 equiv)
R''
H
CH3CN/H2O, (1/3, v/v)
0°C - rt
4
MeO2C
, 0.2 mmol
5
R'' = OEt, OBut, OBn, Me, Et, NHMe, NH2
O
O
O
O
F
Br
Cl
CO2Et
CO2Et
O
CO2Et
O
CO2Et
O
O
N
N
O
N
O
H
H
N
O
H
O
H
MeO2C
MeO2C
MeO2C
MeO2C
5a,
5b
5c
5d
, 12.5 h, 71%
4.5 h, 81%
, 8 h, 77%
O
,12 h, 68%
O
O
O
CO2Et
F3C
Me
MeO
CO2Et
O
CO2Et
CO2Et
O
O
O
N
Br
N
N
O
N
O
H
O
H
H
H
O
MeO2C
MeO2C
MeO2C
MeO2C
5e
5f
5g
5h
,12 h, 71%
,12 h, 53%
O
,12 h, 75%
O
, 9.5 h, 76%
O
O
MeO
MeO
CO2Et
CO2tBu
CO2Et
CO2Et
O
O
N
O
N
O
N
Me
MeO
N
O
H
H
H
H
O
O
O
MeO2C
MeO2C
MeO2C
MeO2C
[a]
O
5i
5j
5l
,14 h, 78%
O
, 12 h, 72%
O
, 24 h, 84%
O
5k
, 50 min, 88%
EtO2C
O
CO2tBu
CO2Bn
O
CO2Me
O
H
N
O
N
O
O
N
S
O
N
O
CO2Me
H
H
H
O
O
MeO2C
MeO2C
MeO2C
[b]
5m
5n
5p
, 17.5 h, 72%
, 24 h, 72%
, 5.5 h,98%
O
5o
,15.5 h, 61%
O
O
O
CONH2
COEt
COMe
O
CONHMe
O
N
O
O
N
O
N
O
N
H
H
H
H
O
O
MeO2C
MeO2C
MeO2C
MeO2C
5t
, 5 h, 62%
5q
5r
5s
, 4.5 h, 71%
, 4 h, 61%
, 3.5 h, 98 %
[a] The reaction was carried out at 40℃. [b] CH3CH2COOH was used as additive instead of AcOH.
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
On the basis of our previous work on AIBX-initiated reactions2b-d, we proposed the mechanism shown in Scheme 5. Firstly,
enone I was generated via AIBX-mediated dehydrogenation. Under the acidic condition, Michael addition of methyl
nitroacetate to enone I could readily happen. Then the yielding adduct II would attack the iodine center of another molecule
of AIBX to give a reactive iodine(V) complex III. Finally, after removal of one molecule of water, the intramolecular oxidative
cyclization would take place which was driven by the release of one AIBA molecule to give 5a. It was feasible that enone I
would directly provide a cycloadduct with methyl nitroacetate which would subsequently be oxidized by a hypervalent
iodine reagent. In order to check this mechanistic feasibility, enone I was prepared separately and was treated with methyl
nitroacetate under the standard reaction conditions except for the absence of AIBX. The desired product 5a was not
detected after 24 h, which indicating that an isoxazoline N-oxide product might not be obtained from the sequence of [3+2]
cycloaddition of enone I with methyl nitroacetate first followed by the oxidation by a hypervalent iodine reagent in the
reaction system. In addition, AIBX could be regenerated (91%) with dimethyl dioxirane after reaction. Notably, the
dehydrogenation of β-keto esters mediated by AIBX was a key step, and it was well known that the dehydrogenation of
ketones was a typical reactivity of IBX. This also indicated that AIBX was present as a cyclic benziodoxole structure under
acidic conditions.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
NMe3
HO
I
O
O
OH
O
O
AIBX
AIBA
AIBX
CO2Et
CO2Et
CO2Et
NO2
CO2Et
NO2
I
4a
MeO2C
MeO2C
II
III
O
MeO2C
nitronate
N
O
-H2O
H
O
CO2Me
O
N
O
EtO2C
O
O
I
NMe3
CO2Et
O
O
-H
+H
O
O
O
I
N
O
O
CO2Et
NO2
MeO2C
O
5a
MeO2C
Me3N
O
O
CO2Me
O
(2 equiv)
COOMe
O2N
CH3COOH (1 equiv)
CO2Me
N
O
CH3CN/H2O (1/3, v/v)
0°C - rt, 24 h
MeO2C
I
, 0.2 mmol
not detected
Scheme 5. Proposed mechanism
We investigated the transformations of the isoxazoline N-oxides 5. [3+2] cycloaddition of 5a as a 1,3-dipolar substrate with
electron-poor dipolarophile ethyl acrylate readily produced the fused polycyclic isoxazoline 6 in a yield of 97% (Scheme 6).
5a was treated with excessive P(OMe)3 to give the deoxygenated isoxazoline 7 in an excellent yield (Scheme 6b).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
Scheme 6. Transformations of isoxazoline N-oxide 5a
1
2
3
4
5
6
7
8
9
O
CO2Et
O
CO2Et
O
N
O
CO2Et
O
(0.8 ml)
(a)
H
MeO2C
CH2Cl2 (0.8 ml),
reflux, 25 h
N
O
H
MeO2C
CO2Et
, 97% yield
6
5a
, 0.1 mmol, 32 mg
O
O
CO2Et
CO2Et
O
N
O
O
N
P(OMe)3
(1 mL)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b)
Ar, reflux, 15 min
H
H
CO2Me
CO2Me
7
, 84% yield
5a
, 0.15 mmol, 48 mg
Trifluoroacetic acid was successfully employed in the oxidation of alcohols with AIBX, while acetic acid was used in the
efficient formation of isoxazoline N-oxides. Can the use of these two acids be interchanged? The reaction was conducted
with p-nitrobenzyl alcohol under the standard reaction conditions, except for acetic acid in replace of trifluoroacetic acid.
After the reaction ran for 24 h, the p-nitrobenzaldehyde was obtained in a yield of 23%. Compared with the reaction using
trifluoroacetic acid (Scheme 1b), the use of acetic acid significantly reduced the reaction rate and yield. The results showed
that trifluoroacetic acid could activate AIBX and improve the oxidation performance of AIBX better than acetic acid. The
reason for this phenomenon is that trifluoroacetic acid (pKa: 3.5 in DMSO) would release more protons to protonate AIBX
and thus lead to more cyclic benziodoxole structure of AIBX than that with acetic acid (pKa: 12.6 in DMSO). Moreover, to
observe the influence of the acid for the synthesis of isoxazoline N-oxides, the reaction was conducted under the standard
reaction conditions, except for trifluoroacetic acid in replace of acetic acid, which affording the desired isoxazoline N-oxide
in a yield of 22% (Table S1, entry 5). The results showed that acetic acid was suitable for the synthesis of isoxazoline N-
oxides because the reaction with acetic acid gave 81% yield of the isoxazoline N-oxide product (Table S1, entry 2). The
conjugated base of an acid can abstract proton of methyl nitroacetate at the α-position to form the corresponding resonance
stabilized anion (nitronate), which would react with enone I to give a Michael addition product II (Scheme 5). It is known
that the conjugate base (CH3COO⊝) of acetic acid is a stronger one than CF3COO⊝, consequently, CH3COO⊝ could better
abstract proton of methyl nitroacetate at the α-position to produce more nitronate.
Conclusion
In summary, AIBX was re-determined to be a pseudocyclic iodylarene 1B by studying the difference between I-O(2) and I-
O(3) bond length in iodylarenes and theoretical calculation including Mayer bond order and localized orbital locator.
However, the cyclic benziodoxole structure of AIBX could be achieved by adding a Brønsted acid like TFA. From our work on
re-determination of AIBX structure, it was understood that judging whether the hypervalent iodine reagent is cyclized or
not is not an easy task. To determine whether the cyclization or not only by a single criterion would be misleading
sometimes, however, using a combination of various means including the comprehensive analysis of X-ray crystallography
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
of reagents, theoretical calculation, and even the comparison of reagent’s reactivity is more reliable to give the right
structure. This set of methods should be useful for the determination of similar iodine(III/V) heterocyclic structures. As far
as reactivity was concerned, AIBX could effectively facilitate the oxidation of alcohols and the synthesis of isoxazoline N-
oxides under acidic conditions.
1
2
3
4
5
6
7
8
9
Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Information. All the reactions were carried out under atmosphere without any special protection. The distilled CH3CN
and deionized water were used as solvents. The known compounds were synthesized by reported procedures and identified by the
comparison of their NMR spectra with reported data in the literatures. The 1H NMR spectra were recorded at 400 MHz and 13C{1H}
1
NMR spectra were measured at 100 MHz using Bruker AV 400 as instrument; CDCl3 was used as the solvent. H NMR spectra are
reported as follows: chemical shift in ppm (δ) relative to the chemical shift of CDCl3 at 7.26 ppm, multiplicities, coupling constants
(Hz) and integration. 13C{1H}NMR spectra are reported in ppm (δ) relative to the central line of triplet of CDCl3 at 77.00 ppm. IR
spectra were recorded with a FT-IR Bruker EQUINOX55 spectrometer in KBr pellets. High-resolution mass spectroscopy (HRMS)
was performed with a high resolution ESI–FTICR mass spectrometer (Varian 7.0 T). The X-ray diffraction data were collected on
Bruker SMART-1000 CCD diffractometer.
Typical procedure for alcohols oxidation. To a solution of alcohols (0.2 mmol) in HFIP (2 mL) was added AIBX (101 mg, 1.5
equiv) and TFA (23 μL, 1.5 equiv). The reaction mixture was stirred at room temperature and monitored by TLC. After the starting
material was completely consumed, the reaction was quenched with sat. aqueous NaHCO3 (1 mL) and Na2S2O3 (1 mL). The
separated aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried
over anhydrous MgSO4. The solvent was evaporated, and the residue was purified by column chromatography to afford carbonyl
compounds, identical in all respects with a commercial sample.
Hexadecanal (3a).16 Colorless solid, 41.7 mg, 87% yield, m.p. 32-34 °C; 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 2.33-2.37 (m, 2H),
1.53-1.57 (m, 2H), 1.18-1.22 (m, 24 H), 0.81 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 202.8, 43.9, 31.9, 29.6, 29.3, 29.1,
22.7, 22.1, 14.1.
1
4-Nitrobenzaldehyde (3b).17 Beige solid, 31 mg, quantitative yield, m.p. 104-105 °C; H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H),
8.40 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 151.1, 140.0, 130.5, 124.3.
4-Biphenylcarboxaldehyde (3c).17 Colorless solid, 35 mg, 97% yield, m.p. 57-58 °C; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.96
(d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 191.9, 147.2, 139.7, 135.2, 130.2, 129.0, 128.4, 127.7, 127.3.
Piperonal (3d).3c Colorless solid, 32 mg, 83% yield, m.p. 36-38 °C; 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.41 (d, J = 7.9 Hz, 1H),
7.33 (s, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.07 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 153.1, 148.7, 131.8, 128.7, 108.3, 106.9,
102.1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
2-Methylcinnamylaldehyde (3e).18 Yellow liquid, 41.3 mg, 94% yield; 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.54 (d, J = 7.5 Hz,
2H), 7.43 (m, 3H), 7.27 (s, 1H), 2.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 149.8, 138.3, 135.1, 130.0, 129.5, 128.7, 10.9.
2-Octanone (3f).16 Liquid, 38 mg, 99% yield; 1H NMR (400 MHz, CDCl3) δ 2.42 (t, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.28 (m, 8H), 0.88 (t, J
= 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 209.24, 43.71, 31.51, 29.74, 28.76, 23.73, 23.41, 13.93.
1
2
3
4
5
6
7
8
1
Benzophenone (3g).17 Oil, 38 mg, quantitative yield; H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 4H), 7.59 (t, J = 7.4 Hz, 2H),
7.49 (t, J = 7.6 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.7, 137.5, 132.4, 130.0, 128.2.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Para-bromoacetophenone (3h).17 Colorless solid, 45 mg, quantitative yield, m.p. 50-51 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J =
8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 2.59 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.0, 135.8, 131.9, 129.8, 128.3, 26.5.
1
4-Tert-butylcyclohexan-1-one (3i).19 Colorless solid, 33 mg, 87% yield, m.p. 47-49 °C; H NMR (400 MHz, CDCl3) δ 2.45-2.20 (m,
4H), 2.12-2.02 (m, 2H), 1.55-1.36 (m, 3H), 0.90 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 212.5, 46.7, 41.3, 32.4, 27.6.
1
Androstenedione (3j).20 Colorless solid, 39.5 mg, 92% yield, m.p. 170-172 °C; H NMR (400 MHz, CDCl3) δ 5.75 (s, 1H), 2.52-2.29
(m, 5H), 2.16-1.93 (m, 4H), 1.87 (d, J = 12.9 Hz, 1H), 1.78-1.39 (m, 6H), 1.33-1.24 (m, 2H), 1.21 (s, 3H), 1.17-1.06 (m, 1H), 0.92 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 220.2, 199.1, 170.2, 124.0, 53.7, 50.7, 47.4, 38.5, 35.6, 35.6, 35.0, 33.8, 32.5, 31.2, 30.6, 21.6,
20.2, 17.3, 13.6.
Coprostanone (3k).19 Colorless solid, 40 mg, 95% yield, m.p. 126-127 °C; 1H NMR (400 MHz, CDCl3) δ 2.46-2.20 (m, 3H), 2.12-1.93
(m, 3H), 1.85-1.77 (m, 1H), 1.73-1.65 (m, 1H), 1.64-1.45 (m, 5H), 1.45-1.03 (m, 17H), 1.00 (s, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.86 (dd,
J = 6.6, 1.6 Hz, 7H), 0.67 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 212.2, 56.3, 56.2, 53.8, 46.7, 44.7, 42.6, 39.9, 39.5, 38.5, 38.2, 36.1,
35.8, 35.6, 35.4, 31.7, 29.0, 28.2, 28.0, 24.2, 23.8, 22.8, 22.5, 21.4, 18.6, 12.0, 11.5.
1
Benzoin (3l).16 Colorless solid, 36 mg, 85% yield, m.p. 135-137 °C; H NMR (400 MHz, CDCl3) δ 7.93-7.90 (m, 2H), 7.54-7.50 (m,
1H), 7.42-7.38 (m, 2H), 7.34-7.26 (m, 5H), 5.95 (s, 1H), 4.56 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.9, 138.9, 133.9, 133.4,
129.1, 129.1, 128.7, 128.6, 127.7, 76.2.
Benzil (3m).16 Yellow solid, 40 mg, 94% yield, m.p. 94-95 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.2 Hz, 4H), 7.67 (t, J = 7.4 Hz,
2H), 7.52 (t, J = 7.7 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.5, 134.9, 133.0, 129.9, 129.0.
Ethyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4a).2b Yellow oil, 857 mg, 84% yield; the ratio of keto form to enol form is 5:1;
1H NMR (CDCl3, 400 MHz) δ 10.33 (brs, 0.2H), 7.78 (d, J = 7.6 Hz, 1.0H), 7.61-7.65 (m, 1.2H), 7.38-7.52 (m, 2.6H), 4.33 (q, J = 7.2 Hz,
0.4H), 4.25 (d, J = 5.4 Hz, 2.0H), 3.71 (dd, J = 4.0 Hz, 8.4 Hz, 0.9H), 3.53-3.59 (m, 1.4H), 3.38 (dd, J = 8.4 Hz, 17.2 Hz, 1.1H), 1.37 (t, J =
7.2 Hz, 0.6H), 1.31 (t, J = 7.2 Hz, 3.1H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.5, 169.1, 153.6, 135.3, 135.2, 129.2, 127.7, 126.7, 1265,
124.6, 124.6, 120.6, 102.4, 61.6, 60.0, 53.2, 32.5, 30.2, 14.4, 14.1.
Ethyl 6-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4b).21 Yellow oil, 833 mg, 75% yield; the ratio of keto form to enol
form is 2.3:1; 1H NMR (CDCl3, 400 MHz) δ 10.33 (brs, 0.2H), 7.47 (dd, J = 8.4, 4.5 Hz, 1.0H), 7.43-7.28 (m, 2.7H), 7.13-7.08 (m, 0.4H),
4.32 (q, J = 7.1 Hz, 0.9H), 4.24 (q, J = 7.1 Hz, 2.0H), 3.75 (dd, J = 8.2, 4.0 Hz, 0.9H), 3.56-3.45 (m, 1.9H), 3.33 (dd, J = 17.1, 8.2 Hz,
1.0H), 1.36 (t, J = 7.1 Hz, 1.3H), 1.30 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 168.9, 168.6, 168.3, 163.6, 163.3,
161.1, 160.9, 148.9, 138.7, 138.6, 138.3, 137.0, 136.9, 127.9, 127.8, 125.7, 125.6, 123.1, 122.9, 116.4, 116.1, 110.3, 110.1, 107.5,
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
107.3, 104.3, , 61.7, 60.1, 54.0, 31.9, 29.6, 14.3, 14.0.
1
2
Ethyl 6-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4c).21 Colorless solid, 1.1 g, 92% yield, m.p. 100-101 °C; the ratio of
3
4
1
keto form to enol form is 2.2:1; H NMR (CDCl3, 400 MHz) δ 10.34 (brs, 0.1H), 7.73 (d, J = 1.9 Hz, 0.9H), 7.61 (t, J = 1.2 Hz, 0.4H),
5
6
7
8
7.59 (d, J = 2.0 Hz, 0.4H), 7.57 (d, J = 2.1 Hz, 0.5H), 7.46 (s, 0.5H), 7.44 (s, 0.4H), 7.38 (d, J = 1.2 Hz, 0.8H), 4.32 (q, J = 7.1 Hz, 0.9H),
4.25 (q, J = 7.2 Hz, 2.0H), 3.75 (dd, J = 8.2, 4.0 Hz, 0.9H), 3.55 (d, J = 4.0 Hz, 0.4H), 3.50 (d, J = 4.7 Hz, 1.5H), 3.34 (dd, J = 17.4, 8.2 Hz,
1.1H), 1.36 (t, J = 7.1 Hz, 1.3H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 168.6, 151.6, 141.1, 138.6, 136.7,
135.4, 134.2, 132.9, 129.2, 127.7, 125.7, 124.3, 120.8, 103.9,61.9, 60.3, 53.7, 32.2, 29.8, 14.4, 14.1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4d).21 Colorless solid, 991 mg, 70% yield, m.p. 92-93 °C; the ratio of
1
keto form to enol form is 2.2:1; H NMR (CDCl3, 400 MHz) δ 10.30 (brs, 0.1H), 7.89 (d, J = 1.8 Hz, 0.9H), 7.77 (d, J = 1.8 Hz, 0.4H),
7.73 (d, J = 1.9 Hz, 0.4H), 7.71 (d, J = 1.9 Hz, 0.5H), 7.52 (dd, J = 8.0, 1.8 Hz, 0.4H), 7.40 (s, 0.5H), 7.38 (s, 0.4H), 7.34 (s, 0.2H), 7.32 (s,
0.2H), 4.32 (q, J = 7.1 Hz, 0.9H), 4.25 (q, J = 7.1 Hz, 2.0H), 3.74 (dd, J = 8.2, 4.0 Hz, 0.9H), 3.52 (d, J = 4.0 Hz, 0.4H), 3.48 (d, J = 4.2 Hz,
1.5H), 3.32 (dd, J = 17.4, 8.2 Hz, 1.0H), 1.36 (t, J = 7.1 Hz, 1.4H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.1,
168.6, 152.1, 141.7, 139.0, 138.1, 137.1, 132.0, 128.1, 127.5, 126.1, 123.8, 122.0, 120.8, 103.8, 61.9, 60.3, 53.6, 32.3, 29.9, 14.4, 14.2.
Ethyl 1-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-indene-2-carboxylate (4e).21 Light brown solid, 748 mg, 55% yield, m.p. 68–
69ꢀ°C; the ratio of keto form to enol form is 1.3:1; 1H NMR (CDCl3, 400 MHz) δ 10.33 (brs, 0.7H), 8.02 (s, 1.0H), 7.87 (s, 0.7H), 7.85
(d, J = 8.2 Hz, 1.0H), 7.63-7.66 (m, 1.7H), 7.55 (d, J = 7.9 Hz, 0.7H), 4.33 (q, J = 7.1 Hz, 1.5H), 4.22-4.28 (m, 2.0H), 3.77 (dd, J = 8.3 Hz,
J = 4.0 Hz, 1.0H), 3.62 (dd, J = 17.7 Hz, J = 3.4 Hz, 1.0H), 3.56 (s, 1.5H), 3.43 (dd, J = 17.7 Hz, J = 8.3 Hz, 1.0H), 1.37 (t, J = 7.1 Hz, 2.3H),
1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 168.6, 156.9, 146.6, 137.7, 135.8, 132.0, 130.9, 129.8, 127.5, 125.2,
124.3, 123.7, 122.1, 117.9, 104.2, 62.2, 60.6, 53.6, 32.9, 30.5, 14.6, 14.3.
Ethyl 6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4f).21 Yellow oil, 928 mg, 85% yield; the ratio of keto form to enol
form is 6.7:1; 1H NMR (CDCl3, 400 MHz) δ 7.57 (s, 0.9H), 7.45 (d, J = 7.8 Hz, 1.1H), 7.39 (d, J = 7.9 Hz, 1.0H), 4.32 (q, J = 7.1 Hz, 0.3H),
4.24 (q, J = 7.7 Hz, 2.0H), 3.71 (dd, J = 8.2, 4.0 Hz, 1.0H), 3.52 (d, J = 4.1 Hz, 0.4H), 3.47 (d, J = 3.0 Hz, 0.9H), 3.32 (dd, J = 17.0, 8.2 Hz,
1.0H), 2.43 (s, 0.4H), 2.40 (s, 3.0H), 1.36 (t, J = 7.1 Hz, 0.4H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.6, 169.2,
151.0, 140.4, 137.8, 137.1, 136.64, 135.4, 130.3, 128.8, 126.2, 124.5, 124.4, 121.0, 102.6, 61.6, 60.0, 53.6, 32.1, 29.9, 21.3, 21.0, 14.4,
14.2.
Ethyl 6-methoxy--1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4g).21 Colorless solid, 1.07 g, 91% yield, m.p. 58-60 °C; the ratio
1
of keto form to enol form is 6.7:1; H NMR (CDCl3, 400 MHz) δ 10.44 (brs, 0.1H) 7.40 (s, 0.4H), 7.38 (s, 0.5H), 7.36-7.33 (m, 0.1H),
7.23 (d, J = 2.6 Hz, 0.5H), 7.20 (dd, J = 7.2, 2.5 Hz, 1.4H), 7.15 (d, J = 2.4 Hz, 0.1H), 4.32 (q, J = 7.1 Hz, 0.3H), 4.25 (q, J = 7.0 Hz, 2.0H),
3.86 (s, 0.4H), 3.83 (s, 3.0H), 3.74 (dd, J = 8.1, 3.8 Hz, 0.9H), 3.48 (d, J = 3.7 Hz, 0.4H), 3.46-3.43 (m, 0.9H), 3.30 (dd, J = 16.9, 8.0 Hz,
1.0H), 1.36 (t, J = 7.1 Hz, 0.4H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 169.2, 169.1, 159.5, 159.0, 146.4,
137.9, 136.3, 135.3, 127.1, 125.2, 124.7, 116.8, 105.5, 104.3, 103.4, 61.5, 59.9, 55.5, 53.9, 31.7, 29.5, 14.3, 14.0.
Ethyl 5-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(4h).21 Colorless solid, 1.23 g, 87% yield, m.p. 47-49 °C; the ratio of
keto form to enol form is 3.3:1; 1H NMR (CDCl3, 400 MHz) δ 7.69 (s, 0.9H), 7.64 (s, 0.4H), 7.62 (s, 0.8H), 7.55-7.49 (m, 1.5H), 4.32 (q,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
J = 7.1 Hz, 0.6H), 4.25 (q, J = 7.0 Hz, 2.0H), 3.71 (dd, J = 8.3, 4.0 Hz, 0.9H), 3.57 (d, J = 4.0 Hz, 0.4H), 3.53 (d, J = 4.0 Hz, 0.6H), 3.50 (s,
0.6H), 3.35 (dd, J = 17.4, 8.3 Hz, 1.0H), 1.37 (t, J = 7.1 Hz, 0.9H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.2,
168.6, 155.1, 144.9, 135.9, 134.1, 131.5, 130.9, 130.1, 129.9, 128.0, 125.8, 123.8, 121.9, 102.8, 61.9, 60.3, 53.3, 32.4, 29.9, 14.4, 14.2.
1
2
3
4
5
6
1
Ethyl 5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4i).21 Yellow oil, 707 mg, 61% yield; H NMR (CDCl3, 400 MHz) δ
7
8
9
7.74-7.66 (m, 1H), 6.97-6.89 (m, 2H), 4.24 (q, J = 6.7 Hz, 2H), 3.90 (s, 3H), 3.70 (dd, J = 8.2, 3.9 Hz, 1H), 3.51 (dd, J = 17.3, 3.9 Hz,
1H), 3.30 (dd, J = 17.3, 8.2 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 169.2, 165.6, 156.5, 128.1, 125.9,
115.7, 109.3, 61.3, 55.5, 53.3, 30.0, 13.9.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 5-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4j).21 Yellow oil, 786 mg, 72% yield; the ratio of keto form to enol
form is 20:1; 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, J = 7.9 Hz, 1.0H), 7.53 (d, J = 7.5 Hz, 0.1H), 7.30 (s, 1.0H), 7.20 (d, J = 7.9 Hz, 1.0H),
4.31 (q, J = 7.2 Hz, 0.1H), 4.24 (q, J = 6.9 Hz, 2.0H), 3.70 (dd, J = 8.2, 4.0 Hz, 0.9H), 3.50 (dd, J = 17.3, 3.8 Hz, 1.2H), 3.31 (dd, J = 17.2,
8.2 Hz, 1.0H), 2.45 (s, 3.0H), 2.44 (s, 0.2H), 1.36 (t, J = 7.1 Hz, 0.2H), 1.31 (t, J = 7.1 Hz, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.0,
169.3, 154.1, 146.7, 133.0 129.0, 127.7, 126.8, 125.4, 124.4, 120.4, 100.0, 61.6, 53.5, 30.1, 22.1, 14.2.
1
Ethyl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4k).21 Colorless solid, 1.24 g, 94% yield, m.p. 141-142 °C; H
NMR (CDCl3, 400 MHz) δ 7.18 (s, 1H), 6.91 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 3.70 (dd, J = 7.9, 3.6 Hz, 1H),
3.45 (dd, J = 17.0, 3.5 Hz, 1H), 3.27 (dd, J = 17.0, 7.9 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 169.4,
156.0, 149.7, 149.2, 128.0, 107.2, 104.8, 61.6, 56.3, 56.1, 53.6, 30.0, 14.2.
o
1
Tert–butyl 1-oxo-2,3-dihydro-1H -indene-2-carboxylate (4l).2b Yellow solid, 760 mg, 66% yield, m.p. 49-51 C; H NMR (CDCl3,
400 MHz) δ 7.76 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 3.62 (dd, J = 3.9 Hz, 8.1 Hz,
1H), 3.47-3.54 (m, 1H), 3.32 (dd, J = 8.1 Hz, 17.1 Hz, 1H), 1.49 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.0, 168.3, 153.7, 143.0,
137.1, 135.4, 135.2, 134.6, 129.0, 127.6, 127.2, 126.6, 126.5, 124.6, 124.5, 123.67, 120.5, 104.0, 82.0, 80.9, 54.3, 32.8, 30.3, 28.4,
28.0.
o
Benzyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (4m).2b Colorless solid, 600 mg, 45% yield, m.p. 43-45 C; the ratio of keto
form to enol form is 4:1; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 0.8H), 7.63 (t, J = 7.4 Hz, 1.0H), 7.54-7.29 (m, 7.7H), 5.32 (s,
0.4H), 5.24 (d, J = 1.8 Hz, 1.6H), 3.79 (dd, J = 8.3, 4.2 Hz, 0.8H), 3.62-3.53 (m, 1.3H), 3.39 (dd, J = 17.2, 8.3 Hz, 0.9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.2, 168.9, 153.5, 143.3, 136.8, 136.1, 135.5, 135.4, 135.2, 129.5, 128.6, 128.6, 128.3, 128.2, 128.1, 128.0,
127.8, 126.8, 126.5, 124.7, 120.8, 102.2, 67.3, 65.7, 53.3, 32.6, 30.2.
Methyl 5-oxo-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxole-6-carboxylate (4n).21 Yellow solid, 646 mg, 69% yield, m.p. 95-97 oC; 1H
NMR (CDCl3, 400 MHz) δ 7.10 (s, 1H), 6.85 (s, 1H), 6.08 (s, 2H), 3.78 (s, 3H), 3.73 (dd, J = 7.9, 3.5 Hz, 1H), 3.43 (dd, J = 17.1, 3.4 Hz,
1H), 3.24 (dd, J = 17.1, 7.9 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 197.1, 169.6, 154.9, 151.4, 148.6, 129.7, 105.5, 102.8, 102.4,
53.5, 52.6, 30.1.
o
Ethyl 1-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalene-2-carboxylate (4o).2c Colorless solid, 335 mg, 88% yield, m.p. 82-83 C;
1H NMR (CDCl3, 400 MHz) δ 9.08 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.68-7.70 (m, 1H), 7.54-7.59 (m,
2H), 4.26-4.29 (m, 2H), 3.84 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 3.65 (dd, J = 4.0 Hz, 16.0 Hz, 1H), 3.45 (dd, J = 8.0 Hz, 16.0 Hz, 1H), 1.33 (t, J
ACS Paragon Plus Environment

Page 15 of 24
The Journal of Organic Chemistry
= 8.0 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 199.9, 169.4, 157.3, 136.7, 129.6, 129.4, 129.3, 128.3, 126.9, 123.9, 123.7, 61.8, 53.9,
30.6, 14.3.
1
2
3
4
5
6
7
8
9
Tert-butyl 4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (4p).2b Slightly yellow solid, 762 mg, 64% yield, mp 62-
64 oC; 1H NMR (CDCl3, 400 MHz) δ 7.32 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 5.1 Hz, 1H), 3.90 (dd, J = 3.0 Hz, 7.2 Hz, 1H), 3.53 (dd, J = 3.0
Hz, 17.4 Hz, 1H), 3.36 (dd, J = 7.2 Hz, 17.4 Hz, 1H), 1.50 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.2, 169.9, 167.8, 144.2, 131.3,
119.9, 82.3, 59.6, 28.5, 28.0.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Acetyl-2,3-dihydro-1H-inden-1-one (4q).2b Yellow solid, 230mg, 44% yield, m.p. 76-77 oC; the ratio of keto form to enol form is
1:6, 1H NMR (400 MHz, CDCl3) δ 13.67 (brs, 0.8H), 7.80 (d, J = 7.6 Hz, 0.9H), 7.70 (t, J = 8.7 Hz, 0.2H), 7.66-7.45 (m, 2.4H), 7.40 (t, J =
7.4 Hz, 1.1H), 3.96 (dd, J = 7.7, 3.3 Hz, 0.2H), 3.72 (dd, J = 17.4, 3.2 Hz, 0.2H), 3.57 (s, 2.0H), 3.12 (dd, J = 17.4, 7.7 Hz, 0.2H), 2.49 (s,
0.5H), 2.17 (s, 3.0H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.3, 199.7, 191.4, 177.4, 154.1, 147.5, 138.2, 135.4, 135.0, 132.7, 127.6,
127.3, 126.6, 125.7, 124.5, 123.1, 110.4, 61.9, 30.2, 30.0, 27.8, 21.0.
2-Propionyl-2,3-dihydro-1H-inden-1-one (4r).2b Yellow solid, 338 mg, 60% yield, m.p. 39-40 oC; the ratio of keto form to enol
form is 1:2.7, 1H NMR (400 MHz, CDCl3) δ 13.67 (brs, 1.0H), 7.81 (d, J = 7.6 Hz, 0.9H), 7.72 (d, J = 7.7 Hz, 0.4H), 7.63-7.49 (m, 2.8H),
7.45-7.33 (m, 1.4H), 3.96 (dd, J = 7.7, 3.3 Hz, 0.3H), 3.73 (dd, J = 17.3, 3.1 Hz, 0.4H), 3.59 (s, 2.0H), 3.19-3.10 (m, 0.7H), 2.72-2.58 (m,
0.4H), 2.48 (q, J = 7.6 Hz, 2.0H), 1.25 (t, J = 7.6 Hz, 3.0H), 1.10 (t, J = 7.2 Hz, 1.1H); 13C{1H} NMR (100 MHz, CDCl3) δ 204.0, 199.9,
190.2, 183.0, 154.3, 147.1, 138.1, 135.3, 135.0, 132.5, 127.5, 127.2, 126.5, 125.6, 124.4, 122.9, 109.5, 60.9, 36.1, 30.0, 28.3, 28.1, 9.7,
7.5.
1-Oxo-2,3-dihydro-1H-indene-2-carboxamide (4s).22 Colorless solid, 35 mg, 10% yield, m.p. 178-180 oC; 1H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.16 (brs, 1H), 5.57 (brs, 1H),
3.77 (dd, J = 17.7, 3.9 Hz, 1H), 3.62 (dd, J = 8.3, 4.1 Hz, 1H), 3.37 (dd, J = 17.7, 8.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 202.7,
168.7, 154.1, 135.6, 135.2, 127.6, 126.7, 124.4, 52.9, 28.5. IR (KBr) ν = 3372, 3083, 2349, 1715, 1648, 1417, 1310, 1203, 1007, 798,
711 cm-1.
N-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (4t).22 Colorless solid, 133 mg, 35% yield, m.p. 150-151 oC;1H NMR (400
MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.15 (brs, 1H), 3.78 (d, J
= 17.6 Hz, 1H), 3.54 (dd, J = 7.8, 3.3 Hz, 1H), 3.35 (dd, J = 17.6, 8.2 Hz, 1H), 2.87 (d, J = 4.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
203.6, 167.0, 154.3, 135.7, 135.3, 127.6, 126.7, 124.3, 52.7, 28.8, 26.5. IR (KBr) ν = 3291, 3172, 2407, 2031, 1643, 1406, 1269, 1094,
754 cm-1.
Typical procedure for synthesis of isoxazoline N-oxides. To a solution of starting materials β-keto esters 4 (0.2 mmol) and
methyl nitroacetate (47.6 mg, 0.4 mmol) in 1:3 (v/v) CH3CN/water (5.3 mL) were added AcOH (11.4 μL, 0.2 mmol) and AIBX (168
mg, 0.5 mmol) successively. The reaction mixture was stirred at 0oC to room temperature and monitored by TLC. After the starting
material 4 was completely consumed, the reaction was quenched with sat. aqueous NaHCO3 (5 mL) and Na2S2O3 (5 mL). The
separated aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL),
dried over anhydrous MgSO4. The solvent was evaporated, and the residue was purified by column chromatography to afford the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
product 5. The aqueous phase was evaporated under vacuum to afford the white solid which was reoxidized by freshly prepared
dimethyldioxirane to regenerate AIBX in 91% yield.
1
2
3
4
5
6
8a-(Ethoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5a). A colorless solid
after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 55 mg, 81% yield, m.p. 132-133 ℃;
7
8
9
1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 5.40 (s,
1H), 4.36 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 192.3, 165.9, 159.1, 149.6, 137.3,
133.0, 130.4, 127.3, 126.3, 108.0, 81.9, 53.2, 52.5, 14.0; IR (KBr) ν = 2957, 2352, 1736, 1640, 1447, 1380, 1244, 1067, 747 cm-1;
HRMS(ESI): calcd for C15H13NNaO7 [M+Na]+ 342.0584, found 342.0588.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8a-(Ethoxycarbonyl)-6-fluoro-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-inde-no[1,2-d]isoxazole 2-oxide (5b). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 52 mg, 77% yield, m.p. 148-
149 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.91 (dd, J = 8.5, 4.4 Hz, 1H), 7.57 (dd, J = 7.0, 2.3 Hz, 1H), 7.49 (td, J = 8.4, 2.4 Hz, 1H), 5.36 (s,
1H), 4.36 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.5, 165.5, 165.0, 62.5, 159.1,
145.3, 135.2, 135.2, 129.3, 129.2, 125.2, 124.9, 112.1, 111.9, 107.7, 82.3, 63.5, 53.2, 52.1, 14.0; IR (KBr) ν = 2954, 1739, 1641, 1479,
1444, 1258, 1063, 978, 867, 746 cm-1; HRMS(ESI): calcd for C15H12FKNO7 [M+K]+ 376.0229, found 376.0232.
6-Chloro-8a-(ethoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5c). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v); 48 mg, 68% yield, m.p. 135-
137 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.90-7.86 (m, 2H), 7.73 (d, J = 8.3 Hz, 1H), 5.36 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.32
(t, J =7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.3, 165.4, 159.0, 147.7, 137.2, 137.1, 134.6, 128.7, 125.8, 107.5, 82.0, 63.5,
53.2, 52.2, 14.0; IR (KBr) ν = 2963, 2356, 1740, 1642, 1446, 1379, 1247, 1203, 1061, 972, 860, 739 cm-1; HRMS(ESI): calcd for
C15H12ClKNO7 [M+K]+ 391.9934, found 391.9938.
6-Bromo-8a-(ethoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5d). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 56 mg, 71% yield, m.p. 138-
139 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 5.33 (s, 1H), 4.35 (q, J = 6.9 Hz, 2H),
3.97 (s, 3H), 1.32 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.2, 165.4, 156.0, 148.2, 140.1, 134.8, 129.0, 128.9, 124.9,
107.5, 81.9, 63.5, 53.3, 52.2, 14.0; IR (KBr) ν = 2954, 2351, 1738, 1640, 1446, 1245, 1112, 1065, 977, 858, 741 cm-1; HRMS(ESI):
calcd for C15H12BrNNaO7 [M+Na]+ 419.9689, 421.9669, found 419.9689, 421.9670.
8a-(Ethoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-6-(trifluoromethyl)-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5e).
A colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 43 mg, 53% yield,
m.p. 140-141 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.21 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 5.45 (s, 1H), 4.37 (q, J =
7.1 Hz, 2H), 3.98 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.4, 165.3, 159.0, 152.4, 133.7, 133.7, 133.4,
133.0, 130.9, 128.8, 128.5, 124.4, 123.4, 121.7, 107.2, 81.8, 63.7, 53.3, 52.5, 14.0. IR (KBr) ν = 3402, 2961, 1745, 1641, 1445, 1382,
1325, 1250, 1199, 1130, 1063, 977, 862, 748 cm-1; HRMS(ESI): calcd for C16H12F3NNaO7 [M+Na]+ 410.0458, found 410.0462.
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
8a-(Ethoxycarbonyl)-3-(methoxycarbonyl)-6-methyl-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5f). A colorless
1
2
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 50 mg, 75% yield, m.p. 144-
3
4
1
145 ℃; H NMR (CDCl3, 400 MHz) δ 7.77 - 7.73 (m, 2H), 7.58 (d, J = 7.9 Hz, 1H), 5.34 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 3.97 (s, 3H),
5
6
7
8
2.47 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 192.4, 165.9, 159.0, 147.1, 140.9, 138.5, 133.2, 127.0, 126.1,
108.2, 82.2, 63.3, 53.1, 52.2, 21.1, 14.0; IR (KBr) ν = 3397, 2960, 2352, 1734, 1640, 1444, 1382, 1252, 1105, 749, 610 cm-1;
HRMS(ESI): calcd for C16H15NNaO7 [M+Na]+ 356.0741, found 356.0745.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8a-(Ethoxycarbonyl)-6-methoxy-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5g).
A
colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 53 mg, 76% yield, m.p.
137-139 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.77 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 5.31 (s, 1H), 4.35 (q,
J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 192.4, 165.8, 161.4, 159.0, 143.0,
134.6, 128.0, 126.5, 108.2, 106.9, 82.4, 63.2, 55.8, 53.1, 51.9, 14.0; IR (KBr) ν = 2949, 2407, 1734, 1637, 1484, 1445, 1387, 1245,
1063, 1017, 971, 860, 747 cm-1; HRMS(ESI): calcd for C16H15KNO8 [M+K]+ 388.0429, found 388.0431.
5-Bromo-8a-(ethoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5h). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 56 mg, 71% yield, m.p. 149-
151 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 5.37 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H),
4.00 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.3, 165.4, 158.9, 150.9, 134.1, 132.9, 131.9, 130.8, 127.2,
107.4, 81.8, 63.9, 53.9, 52.1, 14.0; IR (KBr) ν = 2961, 1738, 1643, 1582, 1444, 1383, 1246, 1059, 975, 908, 855, 747 cm-1;
HRMS(ESI): calcd for C15H12BrNNaO7 [M+Na]+ 419.9689, 421.9669, found 419.9692, 421.9672.
8a-(Ethoxycarbonyl)-5-methoxy-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5i).
A
colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 54 mg, 78% yield,
m.p. 134-136 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.33 (s, 1H), 4.35 (q, J =
7.0 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 190.3, 167.1, 166.0, 159.3, 152.8,
128.0, 125.9, 118.2, 110.7, 108.1, 82.6, 63.3, 56.1, 53.1, 52.1, 14.0; IR (KBr) ν = 3443, 2962, 2032, 1724, 1639, 1598, 1448, 1381,
1264, 1089, 1002, 857, 753 cm-1; HRMS(ESI): calcd for C16H15NNaO8 [M+Na]+ 372.0690, found 372.0695.
8a-(Ethoxycarbonyl)-3-(methoxycarbonyl)-5-methyl-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5j). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 51 mg, 72% yield, m.p. 122-
124 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 5.34 (s, 1H), 4.35 (q, J = 6.4 Hz, 2H),
3.98 (s, 3H), 2.52 (s, 3H), 1.32 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 191.7, 166.0, 159.2, 150.1, 149.3, 131.6, 130.6, 127.6,
126.1, 108.1, 82.3, 63.3, 53.1, 52.3, 22.5, 14.0; IR (KBr) ν = 3438, 2953, 2034, 1732, 1638, 1445, 1380, 1247, 1064, 980, 857, 752
cm-1; HRMS(ESI): calcd for C16H15NNaO7 [M+Na]+ 356.0741, found 356.0743.
8a-(Ethoxycarbonyl)-5,6-dimethoxy-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5k).
A
colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 5/1-3/1, v/v): 71 mg, 88% yield, m.p.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
160-162 ℃; A gram-scale synthesis of 5k: 1.27g, 83% yield; 1H NMR (CDCl3, 400 MHz) δ 7.33 (s, 1H), 7.27 (s, 1H), 5.28 (s, 1H), 4.33
1
(q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 190.9, 166.0,
159.5, 157.3, 151.5, 145.6, 126.0, 108.4, 108.0, 105.6, 82.5, 63.2, 56.6, 56.3, 53.1, 52.0, 14.0; IR (KBr) ν = 3000, 2885, 2818, 2351,
1721, 1637, 1499, 1450, 1375, 1247, 1105, 979, 741, 669 cm-1; HRMS(ESI): calcd for C17H17NNaO9 [M+Na]+ 402.0796, found
402.0801.
2
3
4
5
6
7
8
9
8a-(Tert-butoxycarbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5l). A colorless solid
after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 62 mg, 84% yield, m.p. 138-140 ℃;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (CDCl3, 400 MHz) δ 7.93 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.77 (t, J = 7.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 5.33 (s,
1H), 3.98 (s, 3H), 1.49 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 192.9, 164.6, 159.2, 149.7, 137.1, 133.2, 130.3, 127.3, 126.2, 108.2,
85.4, 81.9, 53.1, 52.3, 27.8; IR (KBr) ν = 3000, 2886, 2351, 1739, 1640, 1452, 1378, 1256, 1154, 975, 747, 670 cm-1; HRMS(ESI):
calcd for C17H17NNaO7 [M+Na]+ 370.0897, found 370.0901.
8a-(Benzyloxy)carbonyl)-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5m).
A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 58 mg, 72% yield, m.p. 113-
115 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H),
7.35 (d, J = 4.2 Hz, 5H), 5.37 (s, 1H), 5.31 (dd, J = 20, 12 Hz, 2H), 3.97 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 192.1, 165.8, 159.0,
149.5, 137.3, 134.2, 133.0, 130.4, 128.8, 128.7, 128.3, 127.4, 126.3, 107.9, 82.0, 68.6, 53.2, 52.4; IR (KBr) ν = 3454, 2352, 1737,
1641, 1449, 1380, 1257, 1075, 975, 745 cm-1; HRMS(ESI): calcd for C20H15NNaO7 [M+Na]+ 404.0741, found 404.0745.
3,9a-Bis(methoxycarbonyl)-9-oxo-3a,9a-dihydro-9H-[1,3]dioxolo[4',5':5,6]indeno [1,2-d]isoxazole 2-oxide (5n). A colorless
solid after purification by flash column chromatography (petroleum ether/EtOAc = 5/1-3/1, v/v): 73 mg, 98% yield, m.p. 189-190
℃; 1H NMR (CDCl3, 400 MHz) δ 7.26 (s, 1H), 7.22 (s, 1H), 6.17 (d, J = 4.3 Hz, 1H), 5.27 (s, 1H), 3.97 (s, 3H), 3.89 (s, 3H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 190.0, 166.3, 159.0, 156.3, 150.5, 147.8, 128.0, 108.0, 106.5, 103.9, 103.3, 82.5, 53.7, 53.2, 52.0; IR (KBr) ν =
2354, 1718, 1637, 1461, 1381, 1241, 1098, 1032, 949, 877, 792, 667 cm-1; HRMS(ESI): calcd for C15H11NNaO9 [M+Na]+ 372.0326,
found 372.0330.
9a-(Ethoxycarbonyl)-7-(methoxycarbonyl)-10-oxo-6b,9a-dihydro-10H-benzo[4,5]indeno[1,2-d]isoxazole 8-oxide (5o).
A
colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 10/1-5/1, v/v): 45 mg, 61% yield,
m.p. 174-175 ℃; 1H NMR (CDCl3, 400 MHz) δ 9.07 (d, J = 8.3 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.5
Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 5.49 (s, 1H), 4.47 – 4.27 (m, 2H), 4.00 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (CDCl3, 100 MHz) δ 192.7, 166.0, 159.2, 152.9, 138.7, 133.7, 130.3, 129.6, 128.6, 128.3, 127.9, 124.4, 123.3, 108.1, 82.3, 63.3,
53.2, 52.2, 14.1; IR (KBr) ν = 2996, 2352, 1713, 1637, 1514, 1443, 1377, 1245, 1092, 975, 830, 752, 671 cm-1; HRMS(ESI): calcd for
C19H15NNaO7 [M+Na]+ 392.0741, found 392.0742.
7a-(Tert-butoxycarbonyl)-3-(methoxycarbonyl)-7-oxo-3a,7a-dihydro-7H-thieno[3',2':4,5]cyclopenta[1,2-d]isoxazole 2-oxide
(5p). A colorless solid after purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 54 mg, 72%
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
yield, m.p. 137-139 ℃; 1H NMR (CDCl3, 400 MHz) δ 7.53 (d, J = 5.1 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 5.32 (s, 1H), 3.97 (s, 3H), 1.51 (s,
1
9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 184.7, 165.9, 164.0, 158.5, 143.0, 134.5, 120.7, 107.3, 86.6, 85.6, 53.1, 50.8, 27.8; IR (KBr) ν =
3513, 3001, 2911, 2845, 2353, 1986, 1731, 1644, 1513, 1463, 1381, 1263, 1103, 975, 749 cm-1; HRMS(ESI): calcd for
C15H15NNaO7S [M+Na]+ 376.0461, found 376.0465.
2
3
4
5
6
7
8
8a-Acetyl-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5q).
A
colorless solid after
purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 44 mg, 72% yield, m.p. 52-53 ℃; 1H NMR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(CDCl3, 400 MHz) δ 7.90 (t, J = 8.4 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 5.49 (s, 1H), 3.98 (s, 3H), 2.59 (s, 3H);
13C{1H} NMR (CDCl3, 100 MHz) δ 201.8, 193.9, 158.9, 150.3, 137.3, 132.8, 130.3, 127.5, 126.1, 109.0, 87.5, 53.1, 50.7, 27.5; IR (KBr)
ν = 2355, 1726, 1637, 1444, 1371, 1255, 1201, 969, 862, 729 cm-1; HRMS(ESI): calcd for C14H11NNaO6 [M+Na]+ 312.0479, found
312.0481.
3-(Methoxycarbonyl)-8-oxo-8a-propionyl-3a,8a-dihydro-8H-indeno[1,2-d] isoxazole 2-oxide (5r). A colorless liquid after
1
purification by flash column chromatography (petroleum ether/EtOAc = 20/3-5/1, v/v): 40 mg, 61% yield; H NMR (CDCl3, 400
MHz) δ 7.89 (t, J = 8.6 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 5.48 (s, 1H), 3.97 (s, 3H), 3.00 (qd, J = 7.1, 1.8 Hz, 2H),
1.14 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 204.6, 194.0, 158.9, 150.4, 137.2, 132.9, 130.3, 127.5, 126.2, 109.0, 87.6,
53.1, 51.1, 33.5, 6.7; IR (KBr) ν = 2947, 2357, 1724, 1638, 1446, 1379, 1250, 746 cm-1; HRMS(ESI): calcd for C15H13NNaO6 [M+Na]+
326.0635, found 326.0640.
8a-Carbamoyl-3-(methoxycarbonyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d] isoxazole 2-oxide (5s). A colorless solid after
purification by flash column chromatography (petroleum ether/EtOAc = 3/1-2/1, v/v): 61 mg, 98% yield, m.p. 174-175 ℃; 1H
NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 6.92 (brs,
1H), 6.33 (brs, 1H), 5.56 (s, 1H), 3.99 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 193.6, 167.7, 158.8, 150.2, 137.3, 133.1, 130.3, 127.3,
126.3, 108.7, 82.7, 53.3, 52.1; IR (KBr) ν = 3368, 3151, 2925, 2352, 2034, 1732, 1686, 1622, 1388, 1256, 1100, 976, 817, 746 cm-1;
HRMS(ESI): calcd for C13H10N2NaO6 [M+Na]+ 313.0431, found 313.0436.
3-(Methoxycarbonyl)-8a-(methylcarbamoyl)-8-oxo-3a,8a-dihydro-8H-indeno[1,2-d]isoxazole 2-oxide (5t). A colorless solid
after purification by flash column chromatography (petroleum ether/EtOAc = 3/1-2/1, v/v): 41 mg, 62% yield, m.p. 204-205 ℃
(decomp.); 1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
6.89 (brs, 1H), 5.56 (s, 1H), 3.99 (s, 3H), 2.97 (d, J = 5.0 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 193.9, 165.6, 158.8, 150.3, 137.3,
133.2, 130.3, 127.3, 126.2, 108.8, 82.8, 53.7, 52.0, 26.5; IR (KBr) ν = 3273, 2929, 2355, 2030, 1732, 1636, 1536, 1381, 1298, 1230,
1150, 971, 855, 795, 716 cm-1; HRMS(ESI): calcd for C14H12N2NaO6 [M+Na]+ 327.0588, found 327.0592.
Typical procedure for [3+2] cycloaddition of isoxazoline N-oxides 5a and ethyl acrylate. Isoxazoline N-oxide 5a (0.1 mmol,
32.0 mg) was dissolved in a mixture of ethyl acrylate (0.8 mL) and dichloromethane (0.8 mL). The resulting mixture was stirred
under reflux until 5a was consumed completely, as monitored by TLC. The solvent and volatile components were removed on a
rotary evaporator under reduced pressure, and the residue was subjected to column chromatographic isolation on silica gel
(petroleum ether/EtOAc = 3/1-2/1, v/v) to give the product 6 as colorless oil in 97% yield (40.5 mg). 1H NMR (CDCl3, 400 MHz) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
7.88 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 5.26 (dd, J = 9.8, 4.5 Hz, 1H), 4.59 (s,
1H), 4.34-4.14 (m, 4H), 3.47 (s, 3H), 3.26 (dd, J = 13.2, 4.4 Hz, 1H), 2.92 (dd, J = 13.0, 9.9 Hz, 1H), 1.26 (m, 7H); 13C{1H} NMR (CDCl3,
100 MHz) δ 196.1, 168.9, 167.8, 166.4, 145.0, 136.1, 135.0, 130.1, 126.4, 125.6, 86.9, 86.7, 80.9, 62.9, 62.0, 56.0, 52.8, 38.9, 14.0,
13.9; IR (KBr) ν = 2921, 2352, 1738, 1596, 1453, 1373, 1272, 1205, 1098, 1029, 923, 831, 752, 673 cm-1; HRMS(ESI): calcd for
C20H21NNaO9 [M+Na]+ 442.1109, found 442.1113.
1
2
3
4
5
6
7
8
General procedure for transformation of isoxazoline N-oxide 5a to the corresponding isoxazolines 7: Isoxazoline N-oxide
5a (0.15 mmol, 48.0 mg) was dissolved in trimethyl phosphite (1.0 mL) in a flask equipped with a condenser. The solution was
well degassed and heated at reflux under Ar. After 5a was completely consumed, the reaction was quenched with 1 N HCl (2.0 mL)
and water (5 mL). The separated aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were dried
over anhydrous MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (petroleum
ether/EtOAc =5/1) to afford the product isoxazolines 7 as colorless oil in 84% yield (38 mg). 1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J
= 7.4 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 5.36 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (CDCl3, 100 MHz) δ 192.9, 166.0, 160.0, 150.4, 149.2, 137.0, 133.0, 130.1, 127.3, 126.5, 93.4, 63.1, 56.9, 53.3, 14.0; IR
(KBr) ν = 2920, 2352, 1730, 1529, 1227, 1039, 910, 749, 671 cm-1; HRMS(ESI): calcd for C15H13NNaO6 [M+Na]+ 326.0635, found
326.0640.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
COMPUTATIONAL DETAILS
All calculations were carried out with the GAUSSIAN 16 packages.23 Geometry optimizations were performed with M06-2X,24 in
which 6-31G(d)25 basis set was used for C, H, O, N and LANL2DZ26 basis set was used for I atom. Frequency analysis calculations
were subsequently performed to verify the optimized geometries to be minima (no imaginary frequency). Localized orbital locator
(LOL) was calculated by Multi WFN 3.5.27
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* E-mail: zhangchi@nankai.edu.cn.
ORCID: 0000-0001-9050-076X
Notes
The authors declare no competing financial interests.
Supporting Information
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
Reaction optimization, X-ray crystallography data, 1H NMR, 13C{1H} NMR spectra and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org. CCDC: 632351-632352(1C); 222124-222125(1D); 200547(1E);
207068 (1F); 268074(1G); 137693(1H); 271726(1I); 1050503(IBX-SO3K); 696745(1J); 683965(IBX).
1
2
3
4
5
6
7
ACKNOWLEDGMENT
8
9
This work was financially supported by The National Natural Science Foundation of China (21472094, 21772096), the National
Key R&D Program of China (2017YFD020030202), and The Tianjin Natural Science Foundation (17JCYBJC20300). We are grateful
to Dr. Li-Qian Cui for his preliminary work in alcohol oxidation. We sincerely thank Prof. Guangxin Liang (Nankai University) for
his valuable advice on the present work.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) For selected reviews, see: (a) Zhdankin V. V.; Stang, P. J. Chemistry of polyvalent iodine. Chem. Rev. 2008, 108, 5299-5358. (b)
Satam, V.; Harad, A.; Rajule, R.; Pati, H. 2-Iodoxybenzoic acid (IBX): an efficient hypervalent iodine reagent. Tetrahedron 2010, 66,
7659-7706. (c) Duschek, A.; Kirsch, S. F. 2-Iodoxybenzoic acid—a simple oxidant with a dazzling array of potential applications.
Angew. Chem., Int. Ed. 2011, 50, 1524-1552. (d) Zhdankin V. V. Organoiodine(V) reagents in organic synthesis. J. Org. Chem. 2011,
76, 1185-1197. (e) Fateh V. Singh F. V.; Wirth, T. Hypervalent iodine-catalyzed oxidative functionalizations including
stereoselective reactions. Chem. - Asian J. 2014, 9, 950-971. (f) Yoshimura, A.; Zhdankin, V. V. Advances in synthetic applications of
hypervalent iodine compounds. Chem. Rev. 2016, 116, 3328-3435.
(2) (a) Cui, L.; Dong, Z.; Liu, K.; Zhang, C. Design, synthesis, structure, and dehydrogenation reactivity of a water-soluble o-
iodoxybenzoic acid derivative bearing a trimethylammonium group. Org. Lett. 2011, 13, 6488-6491. (b) Duan, Y.; Cui, L.; Zuo, L.;
Zhang, C. Recyclable hypervalent-iodine-mediated dehydrogenative α,β’-bifunctionalization of β-keto esters under metal-free
conditions. Chem. - Eur. J. 2015, 21, 13052-13057. (c) Duan, Y.; Zhang, Z.; Zhang, C. Recyclable hypervalent-iodine-mediated
dehydrogenative cyclopropanation under metal-free conditions. Org. Lett. 2016, 18, 6176-6179. (d) Jiang, S.; Yan, T.; Han, Y.; Cui, L.;
Xue, X.; Zhang, C. Hypervalent-iodine-mediated formation of epoxides from carbon(sp2)−carbon(sp3) single bonds. J. Org. Chem.
2017, 82, 11691-11702. (e) Duan, Y.; Jiang, S.; Han, Y.; Sun, B.; Zhang, C. Recent advances in hypervalent iodine chemistry. Youji
Huaxue 2016, 36, 1973-1984 (in Chinese).(f) Han, Y.; Zhang, C. Synthetic application of water-soluble hypervalent iodine reagents
in aqueous media. Tetrahedron Lett. 2018, 59, 3052-3064.
(3) (a) Frigerio, M.; Santagostino, M. A mild oxidizing reagent for alcohols and 1,2-diols: o-Iodoxybenzoic Acid (IBX) in DMSO.
Tetrahedron Lett. 1994, 35, 8019-8022. (b) Wirth, T. IBX—new reactions with an old reagent. Angew. Chem., Int. Ed. 2001, 40,
2812-2814. (c) More, J. D.; Finney, N. S. A simple and advantageous protocol for the oxidation of alcohols with o-iodoxybenzoic acid
(IBX). Org. Lett. 2002, 4, 3001-3003. (d) Uyanik, M.; Ishihara, K. Hypervalent iodine-mediated oxidation of alcohols. Chem. Commun.
2009, 2086-2099.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
(4) (a) Barton, D. H. R.; Godfrey, C. R. A.; Morzycki, J. W.; Motherwell, W. B.; Godfrey, C. R. A. Observations on the chemistry of the
iodoxy group. Tetrahedron Lett. 1982, 23, 957-960. (b) Zhdankin, V. V.; Koposov, A. Y.; Netzel, B. C.; Yashin, N. V.; Rempel, B. P.;
Ferguson, M. J.; Tykwinski, R. R. IBX amides: a new family of hypervalent iodine reagents. Angew. Chem., Int. Ed. 2003, 42, 2194-
2196. (c) Zhdankin, V. V.; Litvinov, D. N.; Koposov, A. Y.; Luu, T.; Ferguson, M. J.; McDonald, R.; Tykwinski, R. R. Preparation and
structure of 2-iodoxybenzoate esters: soluble and stable periodinane oxidizing reagents. Chem. Commun. 2004, 106-107. (d)
Zhdankin, V. V.; Koposov, A. Y.; Litvinov, D. N.; Ferguson, M. J.; McDonald, R.; Luu, T.; Tykwinski, R. R. Esters of 2-iodoxybenzoic acid:
hypervalent iodine oxidizing reagents with a pseudobenziodoxole structure. J. Org. Chem. 2005, 70, 6484-6491. (e) Bredenkamp, A.;
Mohr, F.; Kirsch, S. F. Synthesis of isatins through direct oxidation of indoles with IBX-SO3K/NaI. Synthesis 2015, 47, 1937-1943.
(5) (a) Stevenson, P. J.; Treacy, A. B.; Nieuwenhuyzen, M. Preparation of Dess–Martin periodinane—the role of the morphology of
1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide precursor. J. Chem. Soc. Perkin Trans. 2 1997, 589-591. (b) Thottumkara, A. P.;
Vinod, T. K. Synthesis and oxidation reactions of a user- and eco-friendly hypervalent iodine reagent. Tetrahedron Lett. 2002, 43,
569-572. (c) Moorthy, J. N.; Singhal, N.; Senapati, K. Modified o-methyl-substituted IBX: room temperature oxidation of alcohols
and sulfides in common organic solvents. Tetrahedron Lett. 2008, 49, 80-84. (d) Richardson, R. D.; Zayed, J. M.; Altermann, S.; Smith,
D.; Wirth, T. Tetrafluoro-IBA and-IBX: hypervalent iodine reagents. Angew. Chem., Int. Ed. 2007, 46, 6529-6532.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Zhdankin, V. V.; Nemykin, V. N.; Karimov, R. R.; Kazhkenov, Z. Preparation and X-ray crystal structure of 2-iodyl-N ,N-
dialkylaniline oxides: first entry into the heterocyclic system of benziodoxazole. Chem. Commun. 2008, 6131-6133. (b) Moorthy, J.
N.; Senapati, K.; Parida, K. N. 6-Membered pseudocyclic IBX acids: syntheses, X-ray structural characterizations, and oxidation
reactivities in common organic solvents. J. Org. Chem. 2010, 75, 8416-8421. (c) Yoshimura, A.; Yusubov, M. S.; Zhdankin V. V.
Synthetic applications of pseudocyclic hypervalent iodine compounds. Org. Biomol. Chem. 2016, 14, 4771-4781.
(7) (a) Macikenas, D.; Skrzypczak-Jankun, E.; Protasiewicz, J. D. Redirecting secondary bonds to control molecular and crystal
properties of an iodosyl- and an iodylbenzene. Angew. Chem., Int. Ed., 2000, 39, 2007-2009. (b) Nikiforov, V. A.; Karavan, V. S.;
Miltsov, S. A.; Selivanov, S. I.; Kolehmainen, E.; Wegelius, E.; Nissine, M. Hypervalent iodine compounds derived from o-
nitroiodobenzene and related compounds: syntheses and structures. ARKIVOC, 2003, vi, 191-200. (c) Koposov, A. Y.; Nemykin, V. N.;
Zhdankin, V. V. Intra- and intermolecular interactions in the solid state structure of 2-iodylbenzenesulfonamides:
a
heptacoordinated organic iodine(V) compound. New J. Chem. 2005, 29, 998-1000. (d) Meprathu, B. V.; Justik, M. W.; Protasiewicz, J.
D. ortho-Phosphoryl stabilized hypervalent iodosyl- and iodyl-benzene reagents. Tetrahedron Lett. 2005, 46, 5187-5190. (e)
Koposov, A. Y.; Karimov, R. R.; Geraskin, I. M.; Nemykin, V. N.; Zhdankin, V. V. 2-Iodylphenol ethers: preparation, X-ray crystal
structure, and reactivity of new hypervalent iodine(V) oxidizing reagents. J. Org. Chem. 2006, 71, 8452-8458. (f) Koposov, A. Y.;
(8) (a) Mayer, I. Charge bond order and valence in the AB initio SCF theory. Chem. Phys. Lett. 1983, 97, 270-274. (b) Mayer, I. Bond
order and valence indices: a personal account. J. Comput. Chem. 2007, 28, 204-221.
(9) (a) Gillespie, R. J.; Silvi, B. The octet rule and hypervalence: two misunderstood concepts. Coord. Chem. Rev. 2002, 233-234, 53-
62.
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
(10) (a) Schmider, H. L.; Becke, A. D. Chemical content of the kinetic energy density. Journal of Molecular Structure (Theochem),
2000, 527, 51-61. (b) Schmider, H. L.; Becke, A. D. Two functions of the density matrix and their relation to the chemical bond. J.
Chem. Phys. 2002, 116, 3184-3193. (c) Jacobsen, H. Localized-orbital locator (LOL) profiles of chemical bonding. Can. J. Chem. 2008,
86, 695-702.
1
2
3
4
5
6
7
8
9
(11) For the excellent oxidative stability of HFIP, see: Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J.
Hexafluoroisopropanol as a highly versatile solvent. Nature Reviews Chemistry, 2017, 1, No. 0088. Two strong electron-
withdrawing trifluoromethyl groups and the steric hindrance of HFIP would result in significantly decreased nucleophilicity
of HFIP, which would hamper the oxidation of HFIP by AIBX.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) (a) Zhu, C.; Sun, X.; Deng, X.; Zheng, J.; Tang, Y. Synthesis of isoxazoline N-oxides and its application in the formal synthesis of
dehydroclausenamide. Tetrahedron 2008, 64, 5583-5589. (b) Zhong, C.; Gautam, L. N. S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X.
Concise asymmetric synthesis of fully substituted isoxazoline-N-oxide through Lewis base catalyzed nitroalkene activation. Chem. -
Eur. J. 2010, 16, 8605-8609. (c) Mosher, M. D. Non-dipolar cyclization methods for the preparation of 2-isoxazolines and 2-
isoxazoline N-oxides. Current Organic Synthesis, 2011, 8, 645-658.
(13) (a) Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. One-pot direct conversion of 2,3-epoxy alcohols into enantiomerically
pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides. Org. Lett. 2001, 3, 727-729. (b) Righi, P.; Scardovi, N.; Marotta, E.; Holte, P. t.;
Zwanenburg, B. Solution- and solid-phase synthesis of 4-hydroxy-4,5-dihydroisoxazole derivatives from enantiomerically pure N-
tosyl-2,3-aziridine alcohols. Org. Lett. 2002, 4, 497-500. (c) Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen, K.
A. Achieving molecular complexity by organocatalytic one-pot strategies—a fast entry for synthesis of sphingoids, amino sugars,
and polyhydroxylated α-amino acids. Angew. Chem., Int. Ed. 2009, 48, 6844-6848. (d) Rouf, A.; Sahin, E.; Tanyeli, C. Divergent
synthesis of polysubstituted isoxazoles, isoxazoline N-oxides, and dihydroisoxazoles by a one-pot cascade reaction. Tetrahedron
2017, 73, 331-337.
(14) (a) Jadhav, V. K.; Deshmukh, A. P.; Wadagaonkar, P. P.; Salunkhe, M. M. Sodium perborate: a facile synthesis of 1,2-
benzisoxazole 2-oxides. Synth. Commun. 2000, 30, 1521-1527. (b) Raihan, M. J.; Kavala, V.; Habib, P. M.; Guan, Q.; Kuo, C.; Yao, C.
Synthesis of Isoxazoline N-oxides via [hydroxy(tosyloxy)iodo]benzene (HTIB)-mediated oxidative N-O coupling. J. Org. Chem. 2011,
76, 424-434. (c) Kawai, H.; Okusu, S.; Tokunaga, E.; Shibata, N. Enantioselective synthesis of 5-trifluoromethyl-2-isoxazolines and
their N-oxides by [hydroxy(tosyloxy)iodo]benzene-mediated oxidative N–O Coupling. Eur. J. Org. Chem. 2013, 6506-6509.
(15) (a) Zhang, Q.; Sun, J.; Zhang, F.; Yu, B. Synthesis of sugar-fused isoxazoline N-oxides from 2-nitroglycals. Eur. J. Org. Chem. 2010,
3579-3582. (b) Guo, Z.; Xie, J.; Chen, C.; Zhu, W. Asymmetric catalytic [4 + 1] annulations catalyzed by quinidine: enantioselective
synthesis of multi-functionalized isoxazoline N-oxides. Org. Biomol. Chem. 2012, 10, 8471- 8477. (c) Zhou, R.; Duan, C.; Yang, C.; He,
Z. Phosphane-catalyzed [4 + 1] annulation between nitroalkenes and Morita–Baylis–Hillman carbonates: facile synthesis of
isoxazoline N-oxides by phosphorus ylides. Chem. - Asian J. 2014, 9, 1183-1189. (d) Liu, Y.; Li, H.; Zhou, X.; He, Z. P(NMe2)3-
mediated reductive (1+4) annulation reaction of isatins with nitroalkenes: an access to spirooxindolyl isoxazoline N-oxides and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
their corresponding isoxazolines. J. Org. Chem. 2017, 82, 10997-11007. (e) Zhu, C.; Deng, X.; Sun, X.; Zheng, J.; Tang, Y. Highly
enantioselective synthesis of isoxazoline N–oxides. Chem. Commun. 2008, 738-740.
1
2
3
4
5
6
(16) Zhao, X.-F.; Zhang, C. Iodobenzene dichloride as a stoichiometric oxidant for the conversion of alcohols into carbonyl
compounds; two facile methods for its preparation. Synthesis 2007, 551-557.
7
8
9
(17) Imai, S.; Togo, H. Synthetic utility of iodic acid in the oxidation of benzylic alcohols to aromatic aldehydes and ketones.
Tetrahedron 2016, 72, 6948-6954.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) Riemer, D.; Mandaviya, B.; Schilling, W.; Götz, A. C.; Kühl, T.; Finger, M.; Das, S. CO2-catalyzed oxidation of benzylic and allylic
alcohols with DMSO. ACS Catal. 2018, 8, 3030−3034.
(19) Attoui, M.; Vatèle, J. M. TEMPO/NBu4Br-catalyzed selective alcohol oxidation with periodic acid. Synlett 2014, 25, 2923–2927.
(20) Shakir, A. J.; Paraschivescu, C.; Matache, M.; Tudose, M.; Mischie, A.; Spafiu, F.; Ionita, P. A convenient alternative for the
selective oxidation of alcohols by silica supported TEMPO using dioxygen as the final oxidant. Tetrahedron Lett. 2015, 56, 6878–
6881.
(21) Pluta, R.; Krach, P. E.; Cavallo, L.; Falivene, L.; Rueping, M. Metal-free catalytic asymmetric fluorination of keto esters using a
combination of hydrogen fluoride (HF) and oxidant: experiment and computation. ACS Catal. 2018, 8, 2582-2588.
(22) Goerlitzer, K. Investigations on β-ketoesters. Archiv der Pharmazie 1975, 308, 272-286.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.;
Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.;
Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.;
Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin,
R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16, revision A.03; Gaussian Inc.: Wallingford, CT, 2010.
(24) Zhao, Y.; Truhlar, D. G. Density functionals with broad applicability in chemistry. Acc. Chem. Res. 2008, 41, 157-167.
(25) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. Self-consistent molecular-orbital methods. IX. An extended Gaussian-type basis for
molecular-orbital studies of organic molecules. J. Chem. Phys. 1971, 54, 724-728. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-
consistent molecular orbital methods. XII. Further extensions of Gaussian-type basis sets for use in molecular orbital studies of
organic molecules. J. Chem. Phys. 1972, 56, 2257-2261. (c) Hariharan, P. C.; Pople, J. A. The influence of polarization functions on
molecular orbital hydrogenation energies. Theor. Chim. Acta. 1973, 28, 213-222.
(26) Wadt, W. R.; Hay, P. J. Ab initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi.
J. Chem. Phys. 1985, 82, 284-298.
(27) Lu, T.; Chen, F. Multiwfn: A multifunctional wavefunction analyzer. Analyzer. J. Comput. Chem. 2012, 33, 580-592.
ACS Paragon Plus Environment