[3 + 2]-Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles: A Rapid Entry to Oxazolines

Article abstract of DOI:10.1021/acs.joc.9b01166

A novel and efficient [3 + 2] cycloaddition reaction of azaoxyallyl cations and 1,2-benzisoxazoles to give oxazoline derivatives has been developed. The transformation provides a rapid entry to functionalized oxazoline scaffolds under mild and transition-metal-free conditions, which will greatly expand the reaction types of heterocycle chemistry and pave the way for syntheses of bioactive compounds.

Full text of DOI:10.1021/acs.joc.9b01166

Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Article
[3 + 2]-Cycloaddition of Azaoxyallyl Cations with
1,2-Benzisoxazoles: A Rapid Entry to Oxazolines
Juan Feng, Ming Zhao, and Xuanzi Lin
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Jun 2019
Downloaded from http://pubs.acs.org on June 30, 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 26
The Journal of Organic Chemistry
1
2
3
[3 + 2]-Cycloaddition of Azaoxyallyl Cations with 1,2-
4
5
6
7
Benzisoxazoles: A Rapid Entry to Oxazolines
8
9
Juan Feng, a,b,c,* Ming Zhao, a,b,c Xuanzi Lin a
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
a School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
b Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous
Prophylactic of Ministry of Education of China, Beijing, China
c Beijing Laboratory of Biomedical Materials
ABSTRACT: A novel and efficient [3+2] cycloaddition reaction of azaoxyallyl cations and 1,2-benzisoxazoles to give
oxazoline derivatives has been developed. The transformation provides a rapid entry to functionalized oxazoline scaffolds
under mild and transition-metal free conditions, which will greatly expand the reaction types of heterocycle chemistry and
pave the way for syntheses of bioactive compounds.
INTRODUCTION
Oxazolines are privileged structural motifs widely distributed in natural products and pharmaceutics.1 Development of
novel and efficient methods for their synthesis has received considerable attention. Among the synthetic approaches,
cycloaddition reactions display distinct advantages because they involve the formation of multiple bonds in a single step.2
Azaoxyallyl cations, generated in situ from α-halo hydroxamates, have been extensively applied in cycloaddition reactions
as highly efficient 3-atom units.3 Recently, a series of azaoxyallyl cations involved [3+1]-,4 [3+2]-,5 [3+3]-6 and [3+4]-7
cycloaddition reactions have been well developed, which enable facile synthesis of four to seven-membered heterocyclic
scafolds (Scheme 1a). It is important to note that azaoxyallyl cations could be coupled with different cycloaddition partners
either via the C and O termini or via the C and N as reactive sites, affording the corresponding O-alkylated or N-alkylated
products. In 2018, the annulation reactions between azaoxyallyl cations and nitriles or cyanamides to give imidazolones or
2-aminoimidazolones were reported by Wu and co-workers (Scheme 1b).5f Later, Sun and co-workers (Scheme 1c)5g
established that 4-imidazolones could be prepared through a cycloaddition reaction of azaoxyallyl cations and hexahydro-
1,3,5-triazines. While pioneer synthetic approaches mainly focused on exploration of N-alkylated frameworks, O-alkylated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
5
6
7
8
cycloadditions occurred only in some special cases. In 2016, Jeffrey and co-workers disclosed that [3+2] cycloaddition
reaction of azaoxyallyl cations with carbonyl compounds proceeded by initial O-alkylation followed by rearrangement to
the 4-oxazolidinone.5e Moreover, the Zhao’s research group reported cycloaddition reactions of the azaoxyallyl cations, in
which C and O termini were involved for the bond formations.8 Despite these elegant methods, further exploration of new O-
alkylated approaches is still highly desirable.
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
On the other hand, benzisoxazole is a synthetically important and useful motif, characterized by the notable
nucleophilicity of its nitrogen atom. For example, Tang9 and others10 reported that 1,2-benzisoxazoles usually served as a
unique class of aza-[2C]-components in annulation reactions, generating highly valuable scaffolds through cleaving N-O
bond.
Consequently, we envisioned that [3+2]-cycloaddition reaction of azaoxyallyl cations with 1,2-benzisoxazoles would
deliver imidazolones derivatives (Scheme 1d). However, the originally proposed chemistry failed to work as expected.
Instead, a novel cycloaddition was discovered in practice, affording O-alkylated oxazolines as products (Scheme 1d).
Scheme 1. [3+2] Cycloaddition of Azaoxyallyl Cation with Nitrogen Nucleophiles
RESULTS AND DISCUSSION
We began our feasibility studies by examining the reaction between 1,2-benzisoxazole 1a (1.0 equiv) and α-halo
hydroxamate 2a (1.0 equiv) with Na2CO3 in HFIP at room temperature (Table 1, entry 1). The results showed that the
expected N-alkylated imidazolone derivative 3a’ was not observed. Herein, a new oxazoline derivative 3a was detected in
32% yield by careful analysis of the NMR spectroscopic data. This discovery encouraged us to explore furtherly on this
ACS Paragon Plus Environment

Page 3 of 26
1
The Journal of Organic Chemistry
subject, since azaoxyallyl cations underwent C-O annulation reactions to provide new nitrogen heterocycles. Moreover, the
resulting O-alkylated oxazoline derivatives represent an important class of unique heterocycles because of their potential
bioactivities.
2
3
4
5
6
7
8
Table 1. Optimization of Reaction Conditions a
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
Entry
Base
Solvent
Time (h)
Yield b (%)
1
2
HFIP
HFIP
THF
1
1
32 c
83
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
3
24
24
24
24
24
24
24
1
trace
trace
NR
NR
NR
NR
NR
38
4
CH2Cl2
toluene
DMF
DCE
5
6
7
8
i-PrOH
MeOH
TFE
9
10
11
12
13
14
15
16
17
18
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
24
1
21
71
Cs2CO3
NaOH
t-BuOK
DBU
1
68
1
85
1
70
1
62
Et3N
1
60
DMAP
1
75
aReaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), base (0.40 mmol) and solvent (1.5 mL). bIsolated yield. c1a (0.20 mmol), 2a
(0.20 mmol), base (0.20 mmol). NR = No Reaction. HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, THF = tetrahydrofuran, DMF = N,N-
dimethylformamide, DCE = dichloroethane, TFE = 2,2,2-trifluoroethanol, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-
dimethylaminopyridine.
To improve the efficiency of the above transformations, we conducted a systematic screening of the reaction conditions
with 1a and 2a as model substrates (Table 1). To our gratification, a notable improvement was obtained by increasing the
loading amount of 2a and Na2CO3, affording 3a in 83% yield (entry 2). Next, the effect of solvent was examined.
Unfortunately, only a trace amount of 3a was obtained by using THF and DCM as the reaction media (entries 3 and 4), while
other solvents such as toluene, DMF, DCE, i-PrOH, MeOH and TFE were not suitable for this reaction and rendered no
conversion (entries 5-10). It was found that the base had a notable influence on the outcomes. After screening a number of
inorganic bases (entries 11-14), NaOH gave the best result, providing 3a in 85% yield. Reactions carried out with organic
bases (entries 15-18) failed to enhance the yields.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
Scheme 2. Scope of 1,2-Benzisoxazoles a,b
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
aReaction conditions: 1 (0.20 mmol), 2a (0.40 mmol) and NaOH (0.40 mmol) in HFIP (1.5 mL) at rt for 1h. b Isolated yield.
Having established the optimal reaction conditions, we sought to explore the scope of the reaction with different 1,2-
benzisoxazoles. As shown in Scheme 2, the reactions of α-halo hydroxamate 2a with a range of 1,2-benzisoxazoles were
carried out, which provided corresponding products in good to excellent yields. The substituted 1,2-benzisoxazoles, either
bearing electron-donating or -withdrawing substituents could undergo the transformations smoothly to afford the
corresponding products (3b-3f) in 69-93% yields. The structure of 3d was unambiguously determined by X-ray
crystallography.11 Additionally, 1,2-benzisoxazoles (1g-m) bearing various substitutes (6-Me, 6-OMe, 6-OTBS, 7-Me, 7-OMe,
7-F, 4-F) underwent the cycloaddition reaction to give products in good to excellent yields (73-90%). Also, we found that
5,7-disubstituted substrates were amenable to this reaction, affording oxazolines 3n and 3o in 86% and 93% yields,
respectively. Moreover, this transformation could also be extended to the 1,2-benzisoxazole bearing aromatic ring
substituent, as shown by the case of 3p.
Figure 1. X-ray Structure of Product 4
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
Curiously, the reaction with t-butyl-disubstituted 1,2-benzisoxazole led to N-alkylated product 4 in 65% yield (Figure 1).
The distinct reactivity will be discussed later. The structure of 4 was unambiguously confirmed by X-ray crystallography.11
Table 2. Scope of α-Halo Hydroxamates a,b
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
aReaction conditions: 1 (0.20 mmol), 2 (0.40 mmol) and NaOH (0.40 mmol) in HFIP (1.5 mL) at rt for 1h. bIsolated yield.
cat 60 oC for 10h.
Next, the scope of α-halohydroxamate partner was also systematically evaluated, as shown in Table 2. Hydroxamates with
various N-protecting groups (2b-d) such as methoxy, ethoxy and allyloxy worked well in this reaction, delivering oxazolines
(3q-s) in 75-83% yields. Unfortunately, no desired cycloaddition product was observed with N-benzyl-2-bromo-2-
methylpropanamide (2e) as substrate. The plausible reason is that the N-benzyl substituent is not sufficient enough to
stabilize the azaoxyallyl cation.6g,7c,12 The reaction with α-halo hydroxamates bearing monoalkyl groups (-Me, -Et) displayed
low reactivity, affording 3u and 3v in 42% and 40% yields at an elevated temperature and a longer reaction time.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
Additionally, cyclohexyl-substituted hydroxamate 2h was also compatible, giving 3w in 65% yield. Moreover, some other
combinations of 1,2-benzisoxazoles and α-halohydroxamates tolerated well in this transformation (3x-3z), providing
functionalized oxazolines.
7
8
Scheme 3. Gram-Scale Experimentsa
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
aThe image in scheme 3 was photographed by Juan Feng.
In order to showcase the potential practicality of this method, two large-scale reaction of 1a (4.5 mmol) and 1d (3.5
mmol) with 2a were performed, the desired products 3a (1.12 g) and 3d (1.10 g) were isolated in 80% and 91% yields
under the optimized conditions (Scheme 3, eq 1 and eq 2).
As extension of our study, the cycloaddition of 3-methyl-substituted 1,2-benzoisoxazoles 5 with α-halo hydroxamates 2
was also investigated (Scheme 4). It was found that the reaction was sensitive to the R3-substituent of 1,2-benzoisoxazole.
Actually, substrates bearing a methyl group at the C-3 position gave inferior results and provided tricyclic imidazolones
only in 13-16% yields.5e,6e
Scheme 4. Scope of α-Halo Hydroxamates a,b
aReaction conditions: 5 (0.20 mmol), 2 (0.40 mmol) and NaOH (0.40 mmol) in HFIP (1.5 mL) at rt for 1h. bIsolated yield.
cat 60 oC for 2h.
However, we were surprised to find that the tricyclic imidazolone derivative 6b could be converted to the amide 7 in
nearly quant yield upon exposure to air, whereas 6a and 6c decomposed slowly in the same condition and afforded only
trace amides (results not shown). The structure of 7 was characterized by X-ray diffraction (Scheme 4).11 Mechanistically,
ACS Paragon Plus Environment

Page 7 of 26
1
The Journal of Organic Chemistry
isolation of amide 7 suggested a mechanism involving cleavage of the C-N bond under condition of trace amount of water,
2
3
4
followed by [1,2]-shift process.
5
6
Scheme 5. Control Experiments and Plausible Mechanisms
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
Since both oxazoline products and imidazolone products could be detected in our reaction processes, to further explore
the mechanism of this reaction, several control experiments were carried out. At first, when 3a was treated with acid
(trifluoroacetic acid or hydrochloric acid) or base (NaOH) at room temperature, or refluxed in HFIP for a long time, no N-
alkylated product 3a’ was detected (Scheme 5a, eq 3). Others have also observed some O-cyclization products failed to
5f
rearrange to N-cyclization products,5e, which suggested that the stability of the products dramatically slowed the
rearrangement. We suspected that the failed rearrangement might arise from hydrogen bond between the hydroxyl and the
N atom in the oxazoline products. Unfortunately, the protected oxazoline failed to rearrange via acid catalysis (Scheme 5a,
eq 4). We proposed an alternative mechanism (Scheme 5b, path b) involving a Kemp isomerization of the benzisoxazole to
2-hydroxybenzonitrile 913, which could then form cycloadduct 3a. However, when 2-hydroxybenzonitrile 9 was tested
under standard conditions, only 15% yield of 3a was observed (Scheme 5a, eq 5). At this point, the process benzisoxazole
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
8
1a could convert to 3a via intermediate benzonitrile 9 might be ruled out. It indicated that benzisoxazoles displayed unique
reactivity in cycloadditon reactions. However, upon treatment with LiOH, oxazoline 3a and imidazolone 3a’ were both
obtained in 28% and 27% yields, respectively (Scheme 5a, eq 6). At the moment, it’s unclear why oxazoline products were
main products, the unexpected reactivity of benzisoxazole and effect of base might result in O-alkylation process. Finally, t-
Butyl-substituted 1,2-benzisoxazole was prepared to further explore the reaction, a mixture of 11 and 11’ was obtained
(Scheme 5a, eq 7). Based on our previous control experiments, we speculated that steric bulk of substrate and base used in
this reaction both had effect on formation of N-alkylated product 4.
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
On the basis of the above control experiments, a plausible mechanism was proposed as illustrated in Scheme 5b. Thus, the
cycloaddition of α-halohydroxamate 2a and 1,2-benzisoxazole 1a could occur through path a. Azaoxyallyl cation
intermediate A, once in situ generated from α-halohydroxamate 2a under basic conditions could react with 1,2-
benzisoxazole 1a to form zwitterionic intermediate B. Next, intramolecular nucleophilic addition of B afforded oxygen-
tricycle C, followed by cleavage of the N-O bond to give the final product 3a.
CONCLUSION
In summary, a highly novel and effective [3+2] cycloaddition reaction between in situ generated azaoxyallyl cations and
1,2-benzisoxazoles has been developed, which provides a useful method for access of a series of new oxazoline derivatives
in excellent yields. More significantly, this transformation was conducted under transition metal free conditions. The
biological activity of these oxazolines and further application of these strategies are currently underway in our laboratory.
EXPERIMENTAL SECTION
General Information.
1H NMR, 13C NMR and 19F NMR spectra were recorded on Bruker AV300 spectrometer. TMS was used as internal standard
for 1H NMR (7.26 ppm), and solvent signal was used as reference for 13C NMR (CDCl3, 77.16 ppm). Chemical shift values (δ)
are expressed in ppm downfield relative to internal standard (tetramethylsilane at 0 ppm). Multiplicities are indicated as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), brs (broad singlet), td (triple doublet) and qd (quarter doublet).
Coupling constants are reported in hertz (Hz). Analytical thin layer chromatography (TLC) was performed on SILICYCLE
pre-coated TLC plates (silica gel 60 F-254, 0.25 mm). Visualization was accomplished with UV light and/or KMnO4 staining
solutions. For chromatographic purification, 200-300 mesh silica gel (Qingdao, China) was employed. Infrared spectra (IR)
were recorded on a Thermo Scientific Nicolet iS5 FT-IR spectrophotometer and reported as wavelength numbers (cm−1).
Melting points were determined using a Stanford Research Systems DigiMelt MPA-160 capillary melting point apparatus.
Solvent purification was conducted according to Purification of Laboratory Chemicals (Peerrin, D. D.; Armarego, W. L. and
Perrins, D. R., Pergamon Press: Oxford, 1980). Yields refer to chromatographically and spectroscopically (1H NMR)
ACS Paragon Plus Environment

Page 9 of 26
1
The Journal of Organic Chemistry
homogeneous materials. The HRMS measurements were recorded on ICR (Fourier transform ion cyclotron resonance,
2
3
4
FTICR) analyzer using an ESI source.
5
6
7
8
General Procedures for Synthesis of 1, 2-Benzisoxazoles.9,10b,14 A mixture of Ph3P (1.5 mmol, 1.5 equiv) and DDQ (1.5
mmol, 1.5 equiv) in dry CH2Cl2 (5 mL) was stirred at room temperature for 1 min. Salicylaldoxime (1.0 mmol, 1.0 equiv) was
then added. The color of the reaction mixture changed from green to brown in 1 min. GC or TLC monitoring showed
completion of the reaction, and the solvent was evaporated. Column chromatography of the crude mixture on silica gel
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
using n-hexane and ethyl acetate (20:1) as eluent gave the desired 1,2-benzisoxazoles. All of the 1,2-benzisoxazoles
14a
compounds 1a-1p were prepared according to literature procedures
and the data were matched with reported
values.9,10b,14
General Procedures for Synthesis of α-Halo Hydroxamates.5b,5h,6b,7a To a suspension of the O-benzyloxyamine
hydrochloride or benzylamine (3.0 mmol, 1.0 equiv) and triethylamine (3.0 mmol, 1.0 equiv) in CH2Cl2 (0.25 M) was added
dropwise the alpha-haloacid halide (3.0 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at this temperature until
TLC analysis revealed complete consumption of starting material. The mixture was warmed to room temperature and
quenched with water. The organic phase was washed 3x with water, dried over sodium sulfate, filtered and evaporated.
Purification via flash column chromatography (CH2Cl2) provided the α-halohydroxamates as colorless solids. All of the α-
7a
halohydroxamates 2a-2h were prepared according to literature procedures and the data were matched with reported
values.5b,7a,6b
General Procedures for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles. A mixture of 1,2-
benzisoxazole 1 (0.20 mmol, 1.0 equiv), α-bromoamide 2 (0.40 mmol, 2.0 equiv) and NaOH (16.0 mg, 0.40 mmol, 2.0 equiv)
was added HFIP (1.5 mL) and stirred at room temperature for 1 h. After consumption of the 1,2-benzisoxazole 1 monitored
by TLC analysis, the reaction mixture was filtered. Removal of the solvent under vacuum, the resulting residue submitted to
flash chromatography (SiO2, hexane/EtOAc) to obtain the corresponding oxazoline derivative 3.
Experimental Procedure for Scaling Up Reaction. a) A mixture of 1,2-benzisoxazole 1a (535.5 mg, 4.5 mmol, 1.0
equiv), α-bromoamide 2a (2.439 g, 9.0 mmol, 2.0 equiv) and NaOH (360.0 mg, 9.0 mmol, 2.0 equiv) was added HFIP (33.0
mL) and stirred at room temperature for 1 h. After consumption of the 1,2-benzisoxazole 1a monitored by TLC analysis, the
reaction mixture was filtered. Removal of the solvent under vacuum, the resulting residue was submitted to flash
chromatography (SiO2, hexane/EtOAc) to obtain the corresponding oxazoline 3a (1.12 g, 80%). b) A mixture of 1, 2-
benzisoxazole 1d (535.5 mg, 3.5 mmol, 1.0 equiv), α-bromoamide 2a (1.897 g, 7.0 mmol, 2.0 equiv) and NaOH (280 mg, 7.0
mmol, 2.0 equiv) was added HFIP (26.0 mL) and stirred at room temperature for 1 h. After consumption of the 1,2-
benzisoxazole 1d monitored by TLC analysis, the reaction mixture was filtered. Removal of the solvent under vacuum, the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
resulting residue was submitted to flash chromatography (SiO2, hexane/EtOAc) to obtain the corresponding oxazoline 3d
(1.096 g, 91%).
5
6
7
8
Experimental Procedure for Synthesis of 7. The oxazoline derivate 6b (10.0 mg, 0.036 mmol) was concentrated to
remove the solvent under vacuum, which was upon exposure to air over 3 days, affording the amide 7 (10.6 mg, 0.036 mmol)
in nearly quant yield.
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
Experimental Procedure for Control Experiments.
A mixture of 2-hydroxybenzonitrile 9 (24.0 mg, 0.20mmol, 1.0 equiv), α-bromoamide 2a (108.0 mg, 0.40 mmol, 2.0 equiv)
and NaOH (16.0 mg, 0.4 mmol, 2.0 equiv) was added HFIP (1.5 mL) and stirred at room temperature for 1 h. After
consumption of the 2-hydroxybenzonitrile 9 monitored by TLC analysis, the reaction mixture was filtered. Removal of the
solvent under vacuum, the resulting residue was submitted to flash chromatography (SiO2, hexane/EtOAc) to obtain the
corresponding oxazoline 3a (9.3 mg, 0.03 mmol, 15%).
A mixture of 1,2-benzisoxazole 1a (24.0 mg, 0.20 mmol, 1.0 equiv), α-bromoamide 2a (108.0 mg, 0.40 mmol, 2.0 equiv)
and LiOH (9.6 mg, 0.4 mmol, 2.0 equiv) was added HFIP (1.5 mL) and stirred at room temperature for 1 h. After
consumption of the 1,2-benzisoxazole 1a monitored by TLC analysis, the reaction mixture was filtered. Removal of the
solvent under vacuum, the resulting residue was submitted to flash chromatography (SiO2, hexane/EtOAc) to obtain the
corresponding oxazoline 3a (17.1 mg, 28%) and imidazolone 3a’ (16.7 mg, 27%).
Characterization Data for the Products.
Note: 1,2-Benzisoxazoles 1a,14a 1b,9 1c,14b 1d,9 1e,9 1f,14b 1g,14c 1h,14c 1j,14d 1k,14a 1l,14b 1m,14b 1n,14b 1o,10b 1p,14a and 1q14b
are known compounds and the data were matched with reported values. Thus, their H-NMR, 13C-NMR and GC-MS data are
1
not provided. The 1,2-Benzisoxazoles 1i is a new compound, and its spectroscopic data is provided below.
6-((tert-butyldimethylsilyl)oxy)benzo[d]isoxazole (1i): The product was obtained as a colorless oil. IR νmax (film):
2929, 2858, 1615, 1481, 1301 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 8.57 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.02 (s, 1H), 6.85 (dd,
J = 8.5, 1.7 Hz, 1H), 1.00 (s, 10H), 0.24 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 163.9, 158.5, 146.0, 122.1, 118.6, 115.6,
100.3, 25.7, 18.4, -4.32 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C13H20NO2Si 250.1259; found: 250.1258.
ACS Paragon Plus Environment

Page 11 of 26
1
The Journal of Organic Chemistry
(Z)-2-(2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3a). By following General Procedure for [3+2]
Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a (24.0 mg,
0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded product 3a as
2
3
4
5
6
7
8
o
a yellow white solid (52.7 mg, 0.170 mmol, 85 %). mp 78-80 C; IR νmax (film): 2928, 1703, 1642, 1617, 1489, 1373, 1331,
9
1
1305, 1255, 1227, 1194 cm-1; H NMR (CDCl3, 300 MHz): δ = 11.16 (s, 1H), 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.49-7.29 (m, 6H),
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
7.04 (d, J = 8.4 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 5.13 (s, 2H), 1.53 (d, J = 1.1 Hz, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ =
160.5, 160.1, 157.8, 137.3, 134.4, 128.6, 128.5, 128.5, 128.2, 119.3, 117.1, 109.2, 77.2, 67.39, 28.11 ppm; HRMS (ESI) m/z:
[M+H]+ calcd for C18H19N2O3 311.1392; found: 311.1390.
(Z)-2-(2-hydroxy-5-methylphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3b). By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1b (26.6 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3b as a white solid (46.0 mg, 0.142 mmol, 71 %). mp 110-112 C; IR νmax (film): 2921, 1696, 1646,
1620, 1494, 1450, 1290, 1258 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 10.96 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.47-7.28 (m, 5H),
7.21 (dd, J = 8.4, 2.3 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.13 (s, 2H), 2.28 (s, 3H), 1.51 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75
MHz): δ = 160.5, 157.9, 157.8, 137.3, 135.3, 128.5, 128.5, 128.5, 128.2, 128.1, 116.9, 108.7, 77.2, 67.3, 28.1, 20.4 ppm; HRMS
(ESI) m/z: [M+H]+ calcd for C19H21N2O3 325.1544; found: 325.1547.
(Z) -2-(2-hydroxy-5-methoxyphenyl)-4,4-dimethyloxazol-5(4H)-one O- benzyl oxime (3c). By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1c (29.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3c as a white solid (46.9 mg, 0.138 mmol, 69 %). mp 131-133 C; IR νmax (film): 2940, 1700, 1643,
1614, 1493, 1447, 1381, 1295, 1232 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 10.83 (s, 1H), 7.49-7.32 (m, 5H), 7.24 (d, J = 3.0 Hz,
1H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 5.14 (s, 2H), 3.79 (s, 3H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75
MHz): δ = 160.4, 157.7, 154.5, 152.3, 137.3, 128.6, 128.5, 128.2, 122.3, 118.1, 111.2, 108.7, 77.2, 67.4, 56.2, 28.12 ppm;
HRMS (ESI) m/z: [M+H]+ calcd for C19H21N2O4 341.1498; found: 341.1496.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
(Z)-2-(5-chloro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3d): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1d (30.6 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
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
mL) afforded product 3d as a white solid. (64.0 mg, 0.186 mmol, 93 %). mp 136-138 C; IR νmax (film): 2985, 1696, 1651,
1616, 1480, 1452, 1333，1283, 1223 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.17 (s, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.49-7.32 (m,
6H), 6.99 (d, J = 8.9 Hz, 1H), 5.15 (s, 2H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 159.6, 158.6, 157.1, 137.1,
134.3, 128.6, 128.5, 128.2, 127.7, 124.1, 118.7, 110.1, 77.3, 67.5, 28.0 ppm. HRMS (ESI) m/z: [M+H]+ calcd for C18H18ClN2O3
345.0998; found: 345.1000.
(Z)-2-(5-fluoro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3e): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1e (27.4 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 3e as a white solid (56.4 mg, 0.172 mmol, 86%). mp 94-96 oC; IR νmax (film): 2980, 1694, 1649, 1627,
1
1489, 1342, 1279, 1223 cm-1; H NMR (CDCl3, 300 MHz): δ = 10.97 (s, 1H), 7.52-7.32 (m, 6H), 7.15 (ddd, J = 9.0, 7.9, 3.2 Hz,
1H), 6.99 (dd, J = 9.1, 4.4 Hz, 1H), 5.14 (s, 2H), 1.55 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 159.8 (d, J = 3.0 Hz), 157.3,
155.4 (d, J = 237.0 Hz), 156.3 (d, J = 1.5 Hz), 137.2, 128.5, 128.5, 128. 2, 121.6 (d, J = 23.3 Hz), 118.4 (d, J = 7.5 Hz), 114.0 (d, J
= 25.5 Hz), 109.1 (d, J = 8.3 Hz), 77.2, 67.6, 28.0 ppm; 19F NMR (CDCl3, 282 MHz): δ = -124.10--124.17 (m) ppm; HRMS (ESI)
m/z: [M+H]+ calcd for C18H18FN2O3 329.1291; found: 329.1296.
(Z)-2-(2-hydroxy-5-nitrophenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3f): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1f (32.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
ACS Paragon Plus Environment

Page 13 of 26
1
The Journal of Organic Chemistry
o
mL) afforded product 3f as a white solid (64.1 mg, 0.181 mmol, 90 %). mp 139-141 C; IR νmax (film): 2979, 1700, 1650,
1578, 1524, 1477.01, 1339, 1296, 1265, 1221cm-1; 1H NMR (CDCl3, 300 MHz): δ = 12.09 (s, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.31
(dd, J = 9.2, 2.7 Hz, 1H), 7.50-7.29 (m, 5H), 7.13 (d, J = 9.3 Hz, 1H), 5.13 (s, 2H), 1.55 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75
MHz): δ = 164.9, 159.6, 156.3, 140.2, 137.0, 129.6, 128.7, 128.6, 128.4, 125.2, 118.1, 109.1, 77.5, 67.7, 28.1 ppm; HRMS (ESI)
m/z: [M+H]+ calcd for C18H18N3O5 356.1240; found: 356.1241.
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
(Z)-2-(2-hydroxy-4-methylphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3g). By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1g (26.6 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 3g as a yellow oil (47.3 mg, 0.144 mmol, 73 %); IR νmax (film): 2929, 1695, 1641, 1573, 1508, 1337,
1306, 1263, 1193 cm-1; 1H NMR (CDCl3, 300 MHz): δ =11.12 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.50-7.30 (m, 5H), 6.88 (s, 1H),
6.75 (s, 1H), 5.16 (s, 2H), 2.38 (s, 3H), 1.55 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.5, 160.0, 158.0, 145.6, 137.3,
128.5, 128.5, 128.3, 128.1, 120.5, 117.4, 106.5, 77.1, 67.2, 28.1, 22.0 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C19H21N2O3
325.1549; found: 325.1547.
(Z)-2-(2-hydroxy-4-methoxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3h): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1h (29.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3h as a white solid (54.5 mg, 0.160 mmol, 80 %). mp 116-118 C; IR νmax (film): 2938, 1683, 1628,
1575, 1507, 1355, 1270, 1203, 1190cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.33 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.52-7.29 (m,
5H), 6.54 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.8, 2.4 Hz, 1H), 5.13 (s, 2H), 3.82 (s, 3H), 1.52 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75
MHz): δ = 164.7, 162.0, 160.3, 158.0, 137.3, 129.7, 128.5, 128.5, 128.1, 107.2, 102.3, 101.0, 77.1, 67.1, 55.6, 28.2 ppm; HRMS
(ESI) m/z: [M+H]+ calcd for C19H21N2O4 341.1498; found: 341.1496.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
(Z)-2-(4-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3i): By
following General Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a
mixture of 1,2-benzisoxazole 1i (49.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol)
in HFIP (1.5 mL) afforded product 3i as a colorless oil (67.8 mg, 0.154 mmol, 77 %); IR νmax (film): 2929, 1695, 1640, 1498,
1339, 1275, 1175 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.23 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.39 (ddd, J = 16.6, 10.5, 6.8 Hz,
5H), 6.51 (d, J = 2.0 Hz, 1H), 6.43 (dd, J = 8.6, 2.1 Hz, 1H), 5.13 (s, 2H), 1.52 (s, 6H), 1.01 (d, J = 9.2 Hz, 9H), 0.26 (d, J = 7.3 Hz,
6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 161.8, 161.3, 160.4, 158.0, 137.4, 129.7, 128.5, 128.1, 112.4, 108.0, 103.1, 77.1,
67.1, 28.2, 25.7, 18.4, -4.3 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C24H33N2O4Si 441.2202; found: 441.2204.
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
(Z)-2-(2-hydroxy-3-methylphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3j): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1j (26.6 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 3j as a white solid (47.3 mg, 0.146 mmol, 73 %). mp 81-83 oC; IR νmax (film): 2929, 1690, 1638, 1454,
1364, 1334, 1298, 1256, 1193 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.42 (s, 1H), 7.67 (dd, J = 7.9, 1.7 Hz, 1H), 7.50-7.28 (m,
6H), 6.85 (t, J = 7.6 Hz, 1H), 5.15 (s, 2H), 2.32 (s, 3H), 1.55 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.9, 158.4, 158.0,
137.4, 135.4, 128.6, 128.5, 128.2, 126.3, 126.2, 118.8, 108.5, 77.2, 67.4, 28.2, 16.0 ppm; HRMS (ESI) m/z: [M+H]+ calcd for
C19H21N2O3 325.1543; found: 325.1547.
(Z)-2-(2-hydroxy-3-methoxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3k): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1k (29.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3k as a white solid (55.8 mg, 0.164 mmol, 82 %). mp 95-97 C; IR νmax (film): 2948, 1687, 16468,
1470, 1358, 1303, 1250, 1191 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.41 (s, 1H), 7.47-7.28 (m, 6H), 7.02 (dd, J = 8.1, 1.6 Hz,
1H), 6.86 (t, J = 8.0 Hz, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 1.53 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.7, 157.7, 150.3,
ACS Paragon Plus Environment

Page 15 of 26
1
The Journal of Organic Chemistry
148.4, 137.2, 128.5, 128.5, 128.1, 119.9, 118.9, 115.8, 109.3, 77.1, 67.3, 56.3, 28.0 ppm; HRMS (ESI) m/z: [M+H]+ calcd for
2
3
4
C19H21N2O4 341.1499; found: 341.1496.
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
(Z)-2-(3-fluoro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3l): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1l (27.4 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 3l as a colorless oil (59.1 mg, 0.180 mmol, 90 %); IR νmax (film): 2980, 1695, 1649, 1472, 1338, 1300,
1262, 1194 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.27 (s, 1H), 7.48 (dt, J = 8.1, 1.5 Hz, 1H), 7.30 (m, 5H), 7.15 (ddd, J = 10.6,
7.2, 1.6 Hz, 1H), 6.77 (dd, J = 8.1, 4.5 Hz, 1H), 5.05 (s, 2H), 1.46 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.1 (d, J =
3.8 Hz), 157.2, 151.3 (d, J = 244.5 Hz), 148.6 (d, J = 13.4 Hz), 137.1, 128.5, 128.4, 128.2, 123.5 (d, J = 3.8 Hz), 120.4 (d, J = 17.3
Hz), 118.7 (d, J = 6.7 Hz), 111.1 (d, J = 3.8 Hz), 77.1, 67.4, 28.0 ppm; 19F NMR (CDCl3, 282 MHz): δ = -135.83--136.07 (m) ppm;
HRMS (ESI) m/z: [M+H]+ calcd for C18H18FN2O3 329.1293; found: 329.1296.
(Z)-2-(2-fluoro-6-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3m): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1m (27.4 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3m as a white solid (55.1 mg, 0.168 mmol, 84 %). mp 78-80 C; IR νmax (film): 2983, 1701, 1642,
1620, 1457, 1319, 1230, 1191 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.98 (s, 1H), 7.46-7.30 (m, 6H), 6.84 (dt, J = 8.5, 1.0 Hz,
1H), 6.65 (ddd, J = 10.7, 8.3, 1.1 Hz, 1H), 5.14 (s, 2H), 1.53 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 161.6 (d, J = 3.9 Hz),
161.3 (d, J = 263.2 Hz), 159.6 (d, J = 2.2 Hz), 157.5, 137.4, 134.5 (d, J = 12.0 Hz), 128.4, 128.3, 128.0, 113.1 (d, J = 3.8 Hz),
106.9 (d, J = 21.0 Hz), 99.3 (d, J = 12.8 Hz), 77.1, 65.7, 28.0 ppm; 19F NMR (CDCl3, 282 MHz): δ = -107.20--107.30 (m) ppm;
HRMS (ESI) m/z: [M+H]+ calcd for C18H18FN2O3 329.1300; found: 329.1296.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
(Z)-2-(3-bromo-5-chloro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3n): By following
General Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1n (46.4 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
7
8
o
mL) afforded product 3n as a white solid (72.6 mg, 0.172 mmol, 86 %). mp 137-139 C; IR νmax (film): 3078, 1695, 1645,
9
1608, 1445, 1426, 1370, 1323, 1239, 1182cm-1; 1H NMR (CDCl3, 300 MHz): δ = 12.00 (s, 1H), 7.74 (d, J = 3.2 Hz, 1H), 7.66 (d,
J = 3.2 Hz, 1H), 7.47-7.32 (m, 5H), 5.14 (s, 2H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 159.4, 156.6, 155.4, 137.0,
137.0, 128.6, 128.5, 128.3, 127.0, 124.3, 111.6, 110.6, 77.4, 67.5, 28.0 ppm; HRMS (ESI) m/z: [M+H]+ calcd for
C18H17BrClN2O3 423.0102; found: 423.0106.
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
(Z)-2-(3,5-dibromo-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3o): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1o (55.0 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3o as a white solid. (87.1 mg, 0.187 mmol, 93 %). mp 149-151 C; IR νmax (film): 2916, 1693, 1644,
1606, 1433, 1322, 1253, 1298, 1256, 1196 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 12.03 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.79 (d,
J = 2.4 Hz, 1H), 7.50-7.32 (m, 5H), 5.14 (s, 2H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 159.4, 156.6, 155.9, 139.6,
137.0, 129.9, 128.6, 128.5, 128.3, 112.0, 111.2, 110.9, 77.4, 67.5, 28.0 ppm; HRMS (ESI) m/z: [M-H]¯calcd for C18H15Br2N2O3
464.9455; found: 464.9455.
(Z)-2-(2-hydroxynaphthalen-1-yl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (3p): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1p (33.8 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3p as a white solid (38.2 mg, 0.106 mmol, 53 %). mp 144-146 C; IR νmax (film): 2934, 1695, 1620,
1
1607, 1589, 1472, 1471, 1361, 1227, 1207 cm-1; H NMR (CDCl3, 300 MHz): δ = 13.28 (s, 1H), 8.85 (dd, J = 9.0, 1.2 Hz, 1H),
7.88 (d, J = 9.0 Hz, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (ddd, J = 8.7, 6.9, 1.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.43-7.31 (m, 4H),
7.24 (d, J = 9.0 Hz, 1H), 5.20 (s, 2H), 1.59 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 163.0, 162.9, 158.2, 137.6, 135.7,
ACS Paragon Plus Environment

Page 17 of 26
1
The Journal of Organic Chemistry
131.5, 129.1, 128.6, 128.5, 128.1, 128.0, 125.0, 123.8, 119.1, 101.0, 76.9, 65.1, 28.2 ppm; HRMS (ESI) m/z: [M+H]+ calcd for
2
3
4
C22H21N2O3 361.1546; found: 361.1547.
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
(Z)-2-(3,5-di-tert-butyl-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (4): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1q (46.2 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 4 as a white solid. (54.9 mg, 0.130 mmol, 65 %). mp 145-146 C; IR νmax (film): 2929, 1690, 1638,
1454, 1364, 1334, 1298, 1256, 1193 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 12.68 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4
Hz, 1H), 7.43-7.27 (m, 5H), 5.12 (s, 2H), 1.46 (s, 9H), 1.44 (s, 6H), 1.25 (s, 9H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 179.5,
158.9, 157.8, 140.3, 137.2, 132.7, 130.2, 129.7, 128.6, 128.6, 121.9, 109.3, 79.0, 62.7, 35.4, 34.5, 31.6, 29.6, 24.6 ppm; HRMS
(ESI) m/z: [M+H]+ calcd for C26H35N2O3 423.2641; found: 423.2642.
(Z)-2-(2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-methyl oxime (3q): By following General Procedure for
[3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a
(23.8 mg, 0.20 mmol), haloamide 2b (78.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded
product 3q as a white solid (35.1 mg, 0.15 mmol, 75 %). mp 99-101 oC; IR νmax (film): 2935, 1701, 1642, 1493, 1332, 1307,
1255, 1197, 1111 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.13 (s, 1H), 7.78 (dd, J = 8.1, 1.8 Hz, 1H), 7.45-7.37 (m, 1H), 7.03 (d, J
= 7.8 Hz, 1H), 6.95-6.89 (m, 1H), 3.92 (s, 3H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.4, 160.1, 157.4, 134.5,
128.5, 119.3, 117.2, 109.1, 67.3, 63.0, 28.1 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C12H15N2O3 235.1079; found: 235.1077.
(Z)-2-(2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-ethyl oxime (3r): By following General Procedure for [3+2]
Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a (23.8 mg,
0.20 mmol), haloamide 2c (83.6 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded product 3r as a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
o
white solid (41.2 mg, 0.166 mmol, 83 %). mp 87-89 C; IR νmax (film): 2983, 1703, 1642, 1620, 1484, 1335, 1306, 1252,
1230, 1148 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.19 (s, 1H), 7.81 (dd, J = 8.1, 1.8 Hz, 1H), 7.42 (ddd, J = 8.8, 7.3, 1.8 Hz, 1H),
7.03 (dd, J = 8.4, 1.2 Hz, 1H), 6.92 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.54 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H)
ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.5, 160.1, 157.1, 134.4, 128.6, 119.3, 117.1, 109.2, 70.8, 67.2, 28.1, 14.5 ppm;
HRMS (ESI) m/z: [M+H]+ calcd for C13H17N2O3 249.1236; found: 249.1234.
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
(Z)-2-(2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-allyl oxime (3s): By following General Procedure for [3+2]
Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a (23.8 mg,
0.20 mmol), haloamide 2d (88.4 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded product 3s as a
o
white solid (40.0 mg, 0.154 mmol, 77 %). mp 98-100 C; IR νmax (film): 2895, 1704, 1642, 1617, 1494, 1429, 1345, 1307,
1253, 1229, 1200, 1165, 1024, 969 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.15 (s, 1H), 7.80 (dd, J = 7.2, 1.8 Hz, 1H), 7.42 (ddd,
J = 8.7, 7.2, 1.8 Hz, 1H), 7.03 (dd, J = 8.1, 1.2 Hz, 1H), 6.92 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 6.13-5.98 (m, 1H), 5.42-5.23 (m, 2H),
4.59 (dt, J = 6.0, 1.2 Hz, 2H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 160.5, 160.1, 157.6, 134.4, 133.7, 128.6,
119.3, 118.4, 117.1, 109.1, 76.0, 67.4, 28.1 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C14H17N2O3 261.1234; found: 261.1234.
(S,Z)-2-(2-hydroxyphenyl)-4-methyloxazol-5(4H)-one O-benzyl oxime (3u): By following General Procedure for [3+2]
Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a (23.8 mg,
0.20 mmol), haloamide 2f (102.8 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded product 3u as
o
a white solid (24.9 mg, 0.084 mmol, 42 %). mp 83-85 C; IR νmax (film): 2974, 1698, 1647, 1613, 1582, 1487, 1352, 1258,
1157 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.13 (s, 1H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H), 7.49-7.29 (m, 6H), 7.04 (dd, J = 8.4, 1.2
Hz, 1H), 6.93 (td, J = 7.6, 1.2 Hz, 1H), 5.12 (d, J = 2.1 Hz, 2H), 4.82 (q, J = 7.1 Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR
(CDCl3, 75 MHz): δ = 162.5, 160.1, 155.5, 137.4, 134.6, 128.6, 128.6, 128.5, 128.2, 119.3, 117.2, 109.1, 77.1, 61.1, 20.5 ppm;
HRMS (ESI) m/z: [M+H]+ calcd for C17H17N2O3 297.1235; found: 297.1234.
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(S,Z)-4-ethyl-2-(2-hydroxyphenyl)oxazol-5(4H)-one O-benzyl oxime (3v): By following General Procedure for [3+2]
Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a (23.8 mg,
0.20 mmol), haloamide 2g (108.4 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded product 3v as
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
a white solid (24.8 mg, 0.08 mmol, 40%). mp 84-86 C; IR νmax (film): 2967, 1693, 1645, 1615, 1485, 1464, 1342, 1260,
1227, 1157 cm-1; H NMR (CDCl3, 300 MHz): δ = 11.21 (s, 1H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H), 7.48-7.28 (m, 6H), 7.04 (dd, J =
1
8.4, 1.2 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 5.13 (s, 2H), 4.74 (dd, J = 6.9, 5.1 Hz, 1H), 2.05-1.88 (m, 1H), 1.87-1.74 (m, 1H),
1.00 (t, J = 7.5 Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 162.7, 160.2, 154.5, 137.5, 134.5, 128.6, 128.5, 128.5, 128.2,
119.3, 117.2, 109.0, 77.1, 66.4, 27.8, 9.3 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C18H19N2O3 311.1389; found: 311.1390.
(Z)-2-(2-hydroxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one O-benzyl oxime (3w): By following General Procedure
for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1a
(23.8 mg, 0.20 mmol), haloamide 2h (83.6 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded
product 3w as a colorless oil (124.4 mg, 0.129 mmol, 65%); IR νmax (film): 2932, 1692, 1643, 1488, 1449, 1303, 1256, 1230,
1157, 1007, 751 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.38 (s, 1H), 7.80 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (m, 6H), 7.05 (d, J = 8.4
Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 5.14 (s, 2H), 1.89-1.62 (m, 10H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): 160.3, 160.1, 157.8,
137.4, 134.3, 128.6, 128.5, 128.5, 128.1, 119.2, 117.1, 109.3, 77.1, 70.4, 37.0, 25.1, 21.7 ppm; HRMS (ESI) m/z: [M+H]+ calcd
for C21H23N2O3 351.1701; found: 351.1703.
(Z)-2-(2-hydroxynaphthalen-1-yl)-4,4-dimethyloxazol-5(4H)-one O-allyl oxime (3x): By following General Procedure
for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-benzisoxazole 1p
(33.6 mg, 0.20 mmol), haloamide 2d (88.4 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5 mL) afforded
product 3x as a yellow oil (24.8 mg, 0.08 mmol, 40 %). IR νmax (film): 2979, 1694, 1623, 1610, 1591, 1470, 1419, 1299,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
1252, 1233, 1196, 1001, 976 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 13.29 (s, 1H), 8.83 (dd, J = 8.7, 1.2 Hz, 1H), 7.88 (d, J = 9.0
Hz, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 (ddd, J = 8.7, 6.8, 1.5 Hz, 1H), 7.38 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.23 (d, J = 9.0 Hz,
1H), 6.17-6.00 (m, 1H), 5.42 (dq, J = 17.3, 1.5 Hz, 1H), 5.29 (dq, J = 10.8, 1.2 Hz, 1H), 4.66 (dt, J = 5.7, 1.5 Hz, 2H), 1.61 (s, 6H)
ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 163.0, 162.8, 157.8, 135.7, 133.9, 131.5, 129.1, 128.6, 128.5, 125.0, 123.8, 119.2,
117.8, 101.0, 75.8, 65.1, 28.3 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C18H19N2O3 311.1387; found: 311.1390.
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
(Z)-2-(3-bromo-5-chloro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-allyl oxime (3y): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1n (46.0 mg, 0.20 mmol), haloamide 2d (88.4 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3y as a white solid (67.7 mg, 0.182 mmol, 91 %). mp 147-149 C; IR νmax (film): 2942, 1698, 1647,
1609, 1425, 1321, 1240, 1181, 1033, 971 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 11.96 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.65 (d, J
= 2.4 Hz, 1H), 6.11-5.95 (m, 1H), 5.41-5.20 (m, 2H), 4.58 (dt, J = 5.7, 1.5 Hz, 2H), 1.54 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75
MHz): δ = 159.4, 156.5, 155.5, 137.1, 133.5, 127.0, 124.4, 118.8, 111.6, 110.6, 76.2, 67.6, 28.0 ppm; HRMS (ESI) m/z: [M-H]¯
calcd for C14H13BrClN2O3 370.9802; found: 370.9804.
(Z)-2-(5-chloro-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-methyl oxime (3z): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 1d (30.6 mg, 0.20 mmol), haloamide 2b (78.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
o
mL) afforded product 3z as a white solid. (48.8 mg, 0.182 mmol, 91 %). mp 120-122 C; IR νmax (film): 2939, 1691, 1651,
1
1615, 1575, 1479, 1331, 1282, 1192, 1037, 971 cm-1; H NMR (CDCl3, 300 MHz): δ = 11.11 (s, 1H), 7.74 (d, J = 2.7 Hz, 1H),
7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 1.53 (s, 6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 159.6,
158.6, 156.8, 134.4, 127.6, 124.2, 118.7, 110.1, 67.5, 63.1, 28.0 ppm; HRMS (ESI) m/z: [M-H]¯:calcd for C12H12ClN2O3
267.0544; found: 267.0542.
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
(E)-3,3,8,9b-tetramethyl-9bH-benzo[d]oxazolo[3,2-b]isoxazol-2(3H)-one O-benzyl oxime (6a): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 5a (29.4 mg, 0.20 mmol), haloamide 2a (108.0 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 6a as a colorless oil (8.8 mg, 0.023 mmol, 13%), with the recovery of 17.0 mg (58%) starting material;
IR νmax (film): 2925, 1741, 1492, 1455, 1383, 1255, 1200, 1071, 977 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 7.55-7.45 (m, 2H),
7.41-7.32 (m, 3H), 6.73 (d, J = 8.1 Hz, 1H), 6.68-6.61 (m, 2H), 5.13 (d, J = 3.4 Hz, 2H), 2.29 (s, 3H), 1.75 (s, 3H), 1.48 (s, 3H),
1.19 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ = 172.3, 149.2, 134.7, 134.4, 130.7, 129.9, 129.1, 128.6, 124.3, 117.7,
111.8, 108.6, 79.5, 61.6, 28.1, 24.7, 23.6, 21.3 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C20H23N2O3 339.1705; found: 339.1703.
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
(Z)-3,3,8,9b-tetramethyl-9bH-benzo[d]oxazolo[3,2-b]isoxazol-2(3H)-one O-ethyl oxime (6b): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 5a (29.4 mg, 0.20 mmol), haloamide 2c (83.6 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 6b as a colorless oil (8.3 mg, 0.03 mmol, 15%), with the recovery of 12.4 mg (42%) starting material;
IR νmax (film): 2980, 1740, 1666, 1643, 1491, 1381, 1335, 1251, 1199, 1024, 800 cm-1; 1H NMR (CDCl3, 300 MHz): δ = 6.72
(d, J = 7.8 Hz, 1H), 6.61-6.68 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.75 (s, 3H), 1.49 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H),
1.23 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 172.4, 149.0, 134.2, 130.6, 124.1, 117.5, 111.7, 108.4, 73.1, 61.4, 28.0,
24.4, 23.4, 21.1, 13.7 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C15H21N2O3 277.1550; found: 277.1547.
(Z)-3,3,8,9b-tetramethyl-9bH-benzo[d]oxazolo[3,2-b]isoxazol-2(3H)-one O-allyl oxime (6c): By following General
Procedure for [3+2] Cycloaddition of Azaoxyallyl Cations with 1,2-Benzisoxazoles described above, a mixture of 1,2-
benzisoxazole 5a (29.4 mg, 0.20 mmol), haloamide 2d (88.4 mg, 0.40 mmol), and NaOH (16.0 mg, 0.40 mmol) in HFIP (1.5
mL) afforded product 6c as a colorless oil (9.2 mg, 0.028 mmol, 16 %), with the recovery of 18.9 mg (63%) starting material;
1
IR νmax (film): 2926, 1741, 1491, 1382, 1289, 1252, 1199, 1069, 994, 800 cm-1; H NMR (CDCl3, 300 MHz): δ = 6.72 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
8.1 Hz, 1H), 6.69-6.61 (m, 2H), 6.16-5.98 (m, 1H), 5.45-5.26 (m, 2H), 4.62 (d, J = 6.5 Hz, 2H), 2.28 (s, 3H), 1.75 (s, 3H), 1.48 (s,
3H), 1.22 (s, 3H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 172.4, 149.1, 134.3, 131.7, 130.7, 124.2, 121.2, 117.6, 111.8, 108.5,
78.4, 61.6, 28.1, 24.7, 23.6, 21.3 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C16H21N2O3 289.1546; found: 289.1547.
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
N-ethoxy-2-(N-(2-hydroxy-5-methylphenyl)acetamido)-2-methylpropanamide (7): By following Experimental
Procedure for synthesis of 7. The oxazoline derivate 6b (10.0 mg, 0.036 mmol) was concentrated to remove the solvent
under vacuum, which was upon exposure to air over 3 days, afforded product 7 as a colorless solid (10.6 mg, 0.036 mmol,
o
100 %). mp 150-152 C; IR νmax (film): 3024.60, 2918.56, 1657.26, 1500.86, 1376.21, 1338.57, 1299.30, 1245.16, 1044.53,
825.66; 1H NMR (CDCl3, 300 MHz): δ = 9.83 (s, 1H), 8.61 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H),
4.17-3.98 (m, 2H), 2.28 (s, 3H), 1.75 (s, 6H), 1.32 (t, J = 6.9 Hz, 3H), 1.09 (s, 3H) ; 13C{1H} NMR (CDCl3, 75 MHz): δ = 176.6,
172.5, 153.2, 131.6, 130.2, 129.3, 126.1, 118.0, 72.5, 62.0, 26.9, 23.3, 22.9, 20.4, 13.6; HRMS (ESI) m/z: [M+H]+ calcd for
C15H23N2O4 295.1651; found: 295.1652.
3-(benzyloxy)-2-(2-ethoxyphenyl)-5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one (8): IR νmax (film): 2978, 2929, 1651,
1493, 1453,1192 cm-1; 1H NMR (CDCl3, 400 MHz): δ = 7.77 (dd, J = 7.6, 1.3 Hz, 1H), 7.41 (q, J = 6.1 Hz, 3H), 7.37-7.28 (m, 3H),
6.96 (dd, J = 15.0, 7.9 Hz, 2H), 5.10 (s, 2H), 4.09 (q, J = 6.9 Hz, 2H), 1.50 (d, J = 6.6 Hz, 6H), 1.39 (t, J = 6.9 Hz, 3H) ppm; 13C{1H}
NMR (CDCl3, 100 MHz): δ = 160.7, 158.4, 137.7, 133.2, 131.3, 128.4, 128.4, 127.9, 120.5, 116.1, 113.4, 76.8, 67.9, 65.0, 27.8,
14.7 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C20H23N2O3 339.1708; found: 339.1703.
3-(benzyloxy)-2-(2-hydroxyphenyl)-5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one (3a’): The product was obtained as
a colorless oil (16.7 mg, 0.054 mmol, 27 %). IR νmax (film): 2976, 1744, 1625, 1602, 1491, 1353, 1258 cm-1; 1H NMR (CDCl3,
300 MHz): δ = 8.21 (d, J = 7.5 Hz, 1H), 7.48-7.29 (m, 6H), 7.04 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 5.15 (s, 2H), 1.43 (s,
ACS Paragon Plus Environment

Page 23 of 26
1
The Journal of Organic Chemistry
6H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 179.3, 161.1, 158.2, 133.9, 132.5, 130.5, 129.9, 128.8, 127.8, 118.9, 118.1, 79.1,
2
3
4
63.0, 24.5 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C18H19N2O3 311.1391; found: 311.1390.
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
(Z)-2-(3-(tert-butyl)-2-hydroxyphenyl)-4,4-dimethyloxazol-5(4H)-one O-benzyl oxime (11): The product was
1
obtained as a colorless oil (26.4 mg, 0.072 mmol, 36 %). IR νmax (film): 2959, 2926, 1638, 1456, 1333, 1211 cm-1; H NMR
(CDCl3, 300 MHz): δ = 11.75 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.51-7.29 (m, 6H), 6.85 (t, J = 7.7 Hz, 1H), 5.10 (d, J = 19.3 Hz, 2H),
1.49 (d, J = 28.2 Hz, 15H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 161.2, 159.3, 157.9, 137.6, 137.4, 131.6, 128.5, 128.1,
126.6, 118.6, 109.2, 77.1, 67.4, 35.1, 29.5, 28.2 ppm; HRMS (ESI) m/z: [M+H]+ calcd for C22H27N2O3 367.2017; found:
367.2016.
3-(benzyloxy)-2-(3-(tert-butyl)-2-hydroxyphenyl)-5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one (11’): The product
1
was obtained as a colorless oil (41.7 mg, 0.114 mmol, 57 %). IR νmax (film): 2956, 1746, 1602, 1425, 1252, 1208 cm-1; H
NMR (CDCl3, 300 MHz): δ = 1H NMR (300 MHz, CDCl3) δ 12.96 (s, 1H), 8.17-7.96 (m, 1H), 7.48-7.29 (m, 6H), 6.86 (t, J = 7.9 Hz,
1H), 5.06 (d, J = 37.0 Hz, 2H), 1.46 (d, J = 3.9 Hz, 15H) ppm; 13C{1H} NMR (CDCl3, 75 MHz): δ = 179.3, 160.2, 158.7, 138.1,
132.6, 131.0, 130.4, 129.7, 128.7, 125.8, 118.1, 110.0, 79.0, 62.7, 35.2, 29.5, 24.5 ppm; HRMS (ESI) m/z: [M+H]+ calcd for
C22H27N2O3 367.2012; found: 367.2016.
ASSOCIATED CONTENT
Supporting Information
Spectra data, copies of all new compounds, X-ray crystallography data and CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
*E-mail: fengj18@ccmu.edu.cn
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
Notes
3
4
The authors declare no competing financial interest.
5
6
7
ACKNOWLEDGMENT
8
9
We acknowledge the financial supports from the Beijing Area Major Laboratory of Peptide and Small Molecular Drugs,
Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, China; Beijing
Laboratory of Biomedical Materials;
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) (a) Hashimoto, H.; Imamura, K.; Haruta, J.-i.; Wakitani, K. 4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as Selective
Cyclooxygenase-2 Inhibitors: Enhancement of the Selectivity by Introduction of a Fluorine Atom and Identification of a Potent, Highly
Selective, and Orally Active COX-2 Inhibitor JTE-522. J. Med. Chem. 2002, 45, 1511-1517. (b) Jin, Z. Muscarine, Imidazole, Oxazole, and
Thiazole Alkaloids. Nat. Prod. Rep. 2011, 28, 1143-1191.
(2) (a) Ylijoki, K. E. O.; Stryker, J. M. [5+2] Cycloaddition Reactions in Organic and Natural Product Synthesis. Chem. Rev. 2013, 113,
2244-2266. (b) Richard, R.; Christian, G. B. Arene-Alkene Cycloaddition. Chem. Rev. 2016, 116, 9816-9849. (c) Gothelf, K. V.; Jørgensen, K. A.
Asymmetric 1,3-Dipolar Cycloaddition Reactions. Chem. Rev. 1998, 98, 863-909. (d) Schore, N. E. Transition-Metal-Mediated Cycloaddition
Reactions of Alkynes in Organic Synthesis. Chem. Rev. 1988, 88, 1081-1119.
(3) For review, see: Xuan, J.; Cao, X.; Cheng, X. Advances in Heterocycle Synthesis via [3+m]-Cycloaddition Reactions involving an
Azaoxyallyl cation as the Key Intermediate. Chem. Commun. 2018, 54, 5154-5163.
(4) Li, C.; Jiang, K.; Ouyang, Q.; Liu, T.-Y.; Chen, Y.-C. [3+1]- and [3+2]-Cycloadditions of Azaoxyallyl Cations and Sulfur Ylides. Org. Lett.
2016, 18, 2738-2741.
(5) For selected examples, see: (a) Acharya, A.; Anumandla, D.; Jeffrey, C. S. Dearomative Indole Cycloaddition Reactions of Aza-Oxyallyl
Cationic Intermediates: Modular Access to Pyrroloindolines. J. Am. Chem. Soc. 2015, 137, 14858-14860. (b) DiPoto, M. C.; Hughes, R. P.; Wu,
J. Dearomative Indole (3+ 2) Reactions with Azaoxyallyl Cations − New Method for the Synthesis of Pyrroloindolines. J. Am. Chem. Soc.
2015, 137, 14861-14864. (c) Ji, W.; Yao, L.; Liao, X. Access to the Pyrroloindoline Core via [3+2] Annulation as well as the Application in the
Synthetic Approach to (±)-Minfiensine. Org. Lett. 2016, 18, 628-630. (d) Zhang, K.; Yang, C.; Yao, H.; Lin, A. [3+2] Cycloaddition Reaction of
in Situ Formed Azaoxyallyl Cations with Aldehydes: An Approach to Oxazolidin-4-ones. Org. Lett. 2016, 18, 4618-4621. (e) Acharya, A.;
Montes, K.; Jeffrey, C. S. Access to 4-Oxazolidinones: A (3+2) Cycloaddition Approach. Org. Lett. 2016, 18, 6082-6085. (f) DiPoto, M. C.; Wu,
J. Synthesis of 2-aminoimidazolones and Imidazolones by (3+2) Annulation of Azaoxyallyl Cations. Org. Lett. 2018, 20, 499-501. (g) Ji, D.;
Sun, J. [3+2]-Cycloaddition of Azaoxyallyl Cations with Hexahydro-1,3,5- triazines: Access to 4-Imidazolidinones. Org. Lett. 2018, 20, 2745-
2748. (h) Sun, S. F.; Chen, R. X.; Wang, G. Q.; Wang, J. Sodium Carbonate Promoted [3+2] Annulation of α-Halohydroxamates and
Isocyanates. Org. Biomol. Chem. 2018, 16, 8011-8014.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(6) (a) An, Y.; Xia, H.; Wu, J. Base-controlled [3+3] Cycloaddition of Isoquinoline N-oxides with Azaoxyallyl Cations. Chem. Commun. 2016,
52, 10415-10418. (b) Jia, Q.; Li, D.; Lang, M.; Zhang, K.; Wang, J. 4-Dimethylaminopyridine-Mediated [3+3] Cycloaddition of Aza-oxyallyl
Cations and Nitrones. Adv. Synth. Catal. 2017, 359, 3837-3842. (c) Zhao, H.-W.; Zhao, Y.-D.; Liu, Y.-Y.; Zhao, L.-J.; Feng, N.-N.; Pang, H.-L.;
Chen, X.-Q.; Song, X.-Q.; Du, J. Facile Access to Novel 1,2,4-oxadiazinan-5-ones via [3+3] Cycloaddition of in situ Generated Azaoxyallyl
Cations with Nitrones. RSC Adv. 2017, 7, 12916-12922. (d) Lin, W.; Zhan, G.; Shi, M.; Du, W.; Chen, Y. [3+3] Formal Cycloadditions of
Nitrones from Isatins and Azaoxyallyl Cations for Construction of Spirooxindoles. Chin. J. Chem. 2017, 35, 857-860. (e) Zhang, K.; Xu, X.;
Zheng, J.; Yao, H.; Huang, Y.; Lin, A. [3+3] Cycloaddition of in Situ Formed Azaoxyallyl Cations with 2-Alkenylindoles: An Approach to
Tetrahydro-β-carbolinones. Org. Lett. 2017, 19, 2596-2599. (f) Cheng, X.; Cao, X.; Xuan, J.; Xiao, W.-J. Silver(I)- and Base-Mediated [3+3]-
Cycloaddition of C,N‑Cyclic Azomethine Imines with Aza-oxyallyl Cations. Org. Lett. 2018, 20, 52-55. (g) Cheng, X.; Cao, X.; Zhou, S.-J.; Cai,
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.-G.; He, X.-K.; Xuan, J. Transition-Metal Free Construction of Isoquinoline-fused Triazines Containing Alkenyl CX Bonds. Adv. Synth. Catal.
2019, 361, 1230-1235.
(7) (a) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. Generation and Reactivity of Aza-Oxyallyl Cationic Intermediates: Aza-[4+3]
Cycloaddition Reactions for Heterocycle Synthesis. J. Am. Chem. Soc. 2011, 133, 7688-7691. (b) Acharya, A.; Eickhoff, J. A.; Jeffrey, C. S.
Intramolecular Aza-[4+3] Cycloaddition Reactions of α-Halohydroxamates. Synthesis 2013, 45, 1825-1836. (c) Barnes, K. L.; Koster, A. K.;
Jeffrey, C. S. Trapping the Elusive Aza-oxyallylic Cation: New Opportunities in Heterocycloaddition Chemistry. Tetrahedron Lett. 2014, 55,
4690-4696. (d) Acharya, A.; Eickhof, J. A.; Chen, K.; Catalano, V. J.; Jeffrey, C. S. Access to Bicyclic Hydroxamate Macrocycles via
Intramolecular Aza-(4+3) Cyloaddition Reactions of Aza-oxyallylic Cation Intermediates. Org. Chem. Front. 2016, 3, 330-334.
(8) Zhao, H.-W.; Zhao, Y.-D.; Liu, Y.-Y.; Zhao, L.-J.; Song, X.-Q.; Chen, X.-Q.; Pan, H.-L.; Du, J.; Feng, N.-N. 1,3-Dipolar [3+3] Cycloaddition of
Ahalohydroxamate-based Azaoxyallyl Cations with Hydrazonoyl Chloride-derived Nitrile Imines. RSC Adv. 2017, 7, 55106-55109.
(9) Lei, X.; Gao, M.; Tang, Y. Rh (II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-Triazoles with 2,1-Benzisoxazoles or 1,2-
Benzisoxazoles. Org. Lett. 2016, 18, 4990-4993.
(10) (a) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold-Catalyzed C-H Annulation of Anthranils with Alkynes: A
Facile, Flexible, and Atom-Economical Synthesis of Unprotected 7-Acylindoles. Angew. Chem., Int. Ed. 2016, 55, 794-797. (b) Pandit, Y. B.;
Sahani, R. L.; Liu, R.-S.; Gold-Catalyzed Michael-Type Reactions and [4+2]-Annulations between Propiolates and 1,2-Benzisoxazoles with
Ester-Directed Chemoselectivity. Org. Lett. 2018, 20, 6655-6658. (c) Jin, H.; Tian, B.; Song, X.L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi. A.
S. K. Gold-Catalyzed Synthesis of Quinolines from Propargyl Silyl Ethers and Anthranils through the Umpolung of a Gold Carbene Carbon.
Angew. Chem., Int. Ed. 2016, 55, 12688-12692. (d) Zeng, Z. Y.; Jin, H.; Sekine, K.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold-Catalyzed
Regiospecific C-H Annulation of o-Ethynylbiaryls with Anthranils: π-Extension by Ring-Expansion En Route to N-Doped PAHs. Angew.
Chem., Int. Ed. 2018, 57, 6935-6939. (e) Zeng, Z. Y.; Jin, H.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold (III)-Catalyzed Site-Selective and
Divergent Synthesis of 2-Aminopyrroles and Quinoline-Based Polyazaheterocycles. Angew. Chem., Int. Ed. 2018, 57, 16549-16533.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
(11) X-ray CCDC 1906323 (3d), CCDC 1906324 (4) and CCDC 1906325 (7) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
5
6
7
8
9
(12) Kikugawa, Y.; Shimada, M.; Kato, M.; Sakamoto, T. A New Synthesis of N-Alkoxy-2-ethoxyarylacetamides from N-Alkoxy-N-
chloroarylacetamides with Triethylamine in Ethanol. Chem. Pharm. Bull. 1993, 41, 2192-2194.
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
(13) (a) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. The Physical Organic Chemistry of Benzisoxazoles. I. The Mechanism of the Base-
Catalyzed Decomposition of Benzisoxazoles. J. Org. Chem. 1973, 38, 2294-2301. (b) Kemp, D. S.; Casey, M. L. Physical Organic Chemistry of
Benzisoxazoles. II. Linearity of the Brjáisted Free Energy Relationship for the Base-Catalyzed Decomposition of Benzisoxazoles. J. Am. Chem.
Soc. 1973, 95, 6670-6680. (c) Cullen, W.; Metherell, A. J.; Wragg, A. B.; Taylor, C. G. P.; Williams, N. H.; Ward, M. D. Catalysis in a Cationic
Coordination Cage Using a Cavity-Bound Guest and Surface-Bound Anions: Inhibition, Activation, and Autocatalysis. J. Am. Chem. Soc. 2018,
140, 2821-2828. (d) Stokker, G. Preparation of 1,2-benzisoxazoles from Salicylaldoximes via Trichloroacetyl Isocyanate. J. Org. Chem. 1983,
48, 2613–2615.
(14) (a) Iranpoor, N.; Firouzabadi, H; Nowrouzi, N. A Novel Method for the Highly Efficient Synthesis of 1,2-Benzisoxazoles under
Neutral Conditions Using the Ph3P/DDQ System. Tetrahedron Lett. 2006, 47, 8247-8250. (b) Nimnual, P.; Tummatorn, J.; Thongsornkleeb,
C.; Ruchirawat, S. Utility of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles, Benzoxazoles, and Benzisoxazoles. J. Org.
Chem. 2015, 80, 8657-8667. (c) Poissonnet, G. A Simple and Convenient Synthesis of 1,2-Benzoxazoles Via Intramolecular Mitsunobu
Reaction from Salicylaldoximes and Orthohydroxyarylketoximes. Synthetic Communications. 1997, 27, 3839-3846. (d) Jadhav, P. D.; Lu, X.;
Liu, R.-S. Gold-Catalyzed [5+2]- and [5+1]-Annulations between Ynamides and 1,2-Benzisoxazoles with Ligand-Controlled
Chemoselectivity. ACS Catal. 2018, 8, 9697-9701.
ACS Paragon Plus Environment