R4NHal/NOHSO4: A Usable System for Halogenation of Isoxazoles, Pyrazoles, and beyond

Article abstract of DOI:10.1021/acs.joc.0c02106

A new convenient and versatile halogenating system (R4NHal/NOHSO4), giving straightforward and general access to halogenated 3,5-diaryl- and alkylarylisoxazoles, pyrazoles and electron-rich benzenes from the corresponding scaffolds, is suggested. The method provides excellent regioselectivity, scalability to the gram scale, and a broad scope for both aromatics and halogens. A three-step, one-pot reaction protocol was developed, and a series of 3,5-diaryl-4-haloisoxazoles has been efficiently synthesized from 1,2-diarylcyclopropanes under suggested nitrosating-halogenating conditions.

Full text of DOI:10.1021/acs.joc.0c02106

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Article
R4NHal/NOHSO4: A Usable System for Halogenation of Isoxazoles,
Pyrazoles, and Beyond
Oksana B. Bondarenko,* Georgy L. Karetnikov, Arseniy I. Komarov, Aleksandr I. Pavlov,
and Svetlana N. Nikolaeva
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ABSTRACT: A new convenient and versatile halogenating system (R4NHal/
NOHSO4), giving straightforward and general access to halogenated 3,5-
diaryl- and alkylarylisoxazoles, pyrazoles and electron-rich benzenes from the
corresponding scaffolds, is suggested. The method provides excellent
regioselectivity, scalability to the gram scale, and a broad scope for both
aromatics and halogens. A three-step, one-pot reaction protocol was
developed, and a series of 3,5-diaryl-4-haloisoxazoles has been efficiently
synthesized from 1,2-diarylcyclopropanes under suggested nitrosating−
halogenating conditions.
INTRODUCTION
RESULTS AND DISCUSSIONS
■
■
Halogenated aromatic compounds are valuable synthetic
scaffolds that can be applied as precursors for direct coupling,1
selective preparation of either arylboronic esters or acids, or for
further functionalization of arenes via Grignard reaction2 or the
aromatic nucleophilic substitution. The same methods are used
for the synthesis of substituted hetarenes including isoxazoles
starting from their halogenated precursors.3−5 Haloisoxazoles
and 4-haloisoxazoles, in particular, are widely applied for
functionalization of the isoxazole ring6,7 and for construction of
combinatorial libraries of this heterocycle.8,9 4-Haloisoxazoles
are obtained by electrophilic cyclization of α-alkynyl
oximes10,11 and 1,3-dipolar cycloadditions of 1-halo- or 1-
aluminoalkynes with nitrile oxides;12,13 nevertheless, direct
electrophilic aromatic halogenation of 4H-isoxazoles is the
most available one. A wide range of halogenating agents have
been suggested for the direct synthesis of arylhalogenides;
however, only a few of them are mild.14−16 Most halogenating
systems prescribe rather rigid conditions and have limited
application. Thus, screening literature revealed that the use of a
strongly acidic medium or oxidizing agents is necessary for the
synthesis of 4-haloisoxazoles.17
We began our experiments with the bromination of a model
3,5-diphenylisoxazole 1. Searching for optimal reaction
conditions, we varied the source of halogen and tried several
nitrosating reagents, as well as solvents. We primarily selected a
range of bromides as bromine surrogates, namely, gaseous
hydrogen bromide, as well as potassium, ammonium, and
tetramethylammonium bromides. The reaction of 1 with either
hydrogen or potassium bromides in combination with
nitrosonium chlorosulfate in nitromethane was inefficient,
obviously due to the low solubility of the reactants. However,
the same reaction with ammonium or tetramethylammonium
bromides gave excellent results: isoxazole 1 was smoothly,
quantitatively, and selectively brominated at the C-4 carbon of
the isoxazole ring in reaction with 3 equiv of both Me4NBr/
NOSO3Cl at 20 °C for 20 min. We also screened other
nitrosating reagents including nitrosonium tetrafluoroborate
and nitrosylsulfuric acid. Though all of them provided good
results, we revealed nitrosylsulfuric acid as an oxidant of choice
due to its availability, cheapness, and relative stability. At the
next stage, we examined the influence of temperature, reaction
duration, and the reagent ratio on the transformation of
In our previous investigations dealt with the synthesis of 5-
haloisoxazoles, we found that nitrosonium cation readily
oxidizes bromide anion formed during the reaction, thus
generating electrophilic species that in situ brominate the
isoxazole ring.18,19 This result was put at the core of the study
dealing with the development of new convenient halogenating
systems for electron-rich aromatics.20
Received: September 1, 2020
https://dx.doi.org/10.1021/acs.joc.0c02106
© XXXX American Chemical Society
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Table 1. Halogenation of 3,5-Diphenylisoxazole 1 with R4NHal/NOHSO4: Optimization of the Reaction Conditions
entry
halogen source (equiv)
NOHSO4, equiv
T (°C)
t (h)
product
Hal
conversion
isolated yield (%)
1
2
3
4
5
6
7
8
9
Me4NBr (1.1)
Me4NBr (1.2)
NH4Br (1.2)
Me4NI (1.2)
NH4I (1.2)
1.1
3
3
3
3
3
3
4
3
20
20
20
20
20
20
20
20
20
1
1
3
1
3
1a
1a
1a
1b
1b
1b
1c
1c
1c
Br
Br
Br
I
I
I
Cl
Cl
Cl
30
100
100
100
100
100
45
89
70
87
89
82
I2 (0.6)
2
Me4NCl (1.2)
NH4Cl (1.5)
Me4NCl (3.0)
24
24
24
20
100
87
isoxazole 1 to 4-bromoisoxazole 1a. It was shown that the
excess of both components of the brominating system or even
only the excess of nitrosylsulfuric acid significantly accelerates
the reaction (Table 1, entries 1 and 2): Me4NBr/NOHSO4
taken in a ratio of 1.2:3 equiv per 1 equiv of 1 ensured 100%
conversion of 1 at 20 °C for 1 h and produced 4-
bromoisoxazole 1a in an 89% isolated yield. Changing
Me4NBr for NH4Br under the same reaction conditions gave
100% conversion of 1 in 3 h. Though, in nitromethane, the
reaction proceeds faster and cleaner, DCM, carbon tetra-
chloride, and acetonitrile also can be applied. An important
peculiarity of this reaction process is the workup, in which the
use of successive treatment of the resultant mixture with
aqueous Na2SO3 and water gave the products not requiring
any purification.
Scheme 1. Halogenation of 3,5-Diarylisoxazoles
We next studied the reaction scope against the change of
substitution at the benzene rings. Most of the isoxazoles 1−12
presented at Scheme 1 were smoothly brominated at room
temperature within 1−5 h, depending on the reactivity of the
substrates. Enhancing the temperature accelerates the reac-
tions. For example, the reaction of isoxazoles 8 and 9, bearing
electron-deficient aromatics with 3 equiv of Me4NBr/
NOHSO4, could be completed at 20 °C in 24 h or at 60 °C
in 3 h. Note that, for all studied isoxazoles, we observed high
regioselectivity of halogenation for the isoxazole ring in spite of
the excess of halogenating reagents. An exception is
compounds with strongly electron-donating substituents in
the benzene rings. Thus, in the case of isoxazole 12, 100%
bromination for the isoxazole ring has been already achieved in
30 min of the reaction with 1.2 equiv of both Me4NBr/
NOHSO4 at 20 °C. Treatment of 12 with 3-fold excess of the
reagents for 20 h afforded only double brominated product 13
with a nearly quantitative yield.
We next evaluated the generality of the reaction toward
other halogens. In order to get direct access to 4-
iodoisoxazoles, we changed ammonium bromides for the
corresponding iodine salts. Both ammonium and tetramethy-
lammonium iodides in the presence of nitrosylsulfuric acid
afforded 4-iodo-3,5-diphenylisoxazole 1b with equal success
(Table 1, entries 4 and 5). The excess of nitrosylsulfuric acid in
relation to iodine surrogate is strongly recommended,
especially in the case of EWG-substituted benzene rings
(isoxazoles 6, 8, and 9). The fact is that the deactivated
isoxazole ring is less reactive toward electrophilic halogenation,
and a part of I+ species formed during the redox reaction
recombines with iodide anions of the ammonium salt and is
discarded out of the solution in the form of elemental iodine.
Elevating the temperature slightly promotes the iodination,
unlike the bromination, apparently due to the fact that
elemental bromine itself can be used for the bromination of
isoxazoles.21 However, using an excess of nitrosylsulfuric acid
B
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provides some constant amount of I+ species in the reaction
medium, thus making it possible to rectify the situation and
consequently to afford high yields of 4-iodoisoxazoles (Scheme
1). Due to the low equilibrium concentration of electrophilic
iodine, the Me4NI/NOHSO4 system is very gentle and
selective even for isoxazoles bearing electron-rich benzene
rings. Thus, alkyl-substituted isoxazole 14 was found to be an
equally viable substrate for the reaction to furnish the product
14b in 91% yield. Elemental iodine also can be applied for the
iodination of isoxazoles, and in combination with NOHSO4, it
forms a more active iodinating system. In this case, both iodine
atoms participate in the process; hence, 0.5−0.6 mol of iodine
per mole of isoxazole is enough to complete the reaction
(Table 1, entry 6). This is a notable difference from the NIS
reactions when a large excess of NIS was required for complete
iodination of 3,5-diarylisoxazoles.17 The system I2/NOHSO4
ensures excellent results for isoxazoles with deactivated
benzene rings. The reaction of isoxazole 6 with I2/NOHSO4
taken in a molar ration 1:1.2:3 was completed in 1 h at room
temperature, and the corresponding 4-iodoisoxazole 6b was
obtained in 85% isolated yield, for comparison, conversion of 6
in reaction with Me4NI/NOHSO4 (molar ration 1:1.2:3) for
the same period of time constituted 60%. To test the ability to
scale up the synthesis, gram-scale reactions of isoxazoles 1, 5,
and 6 with either Me4NI/NOHSO4 or I2/NOHSO4 were also
carried out, giving the corresponding 4-iodoisoxazoles 1b, 5b,
and 6b in 72−83% yields.
We were also pleased to discover a general chlorination
procedure for the synthesis of 3,5-diaryl-4-chloroisoxazoles
using ammonium or tetramethytlammonium chlorides. In
detail, the chlorination of isoxazoles proceeds slower in
comparison with the bromination and iodination, apparently
due to the higher oxidation potential of a chloride ion (Table
1, entry 7). In a common case, the reactions should be
performed with 3 equiv of both nitrosylsulfuric acid and
chlorine surrogate relative to isoxazole at room temperature for
an extended reaction time (about 20−24 h), especially for
deactivated substrates. Short-term rather than prolonged
heating of the reaction mixture (30 min at 60 °C then 20
°C) accelerates the reaction resulting in 30% conversion in 3 h
and full completion of the reaction in 20 h. Prolonged heating
may provoke the emission of gaseous chlorine out of the
solution (yellow-green fumes in a reaction vessel), thus
preventing the reaction to complete. As a result of our study,
a series of 3,5-diaryl-4-chloroisoxazoles 1c−7c, 12c, and 15c
was obtained with the same excellent regioselectivity and good-
to-excellent yields (Scheme 1).
Scheme 2. Envisioned Scenario for the Synthesis of 3,5-
Diaryl-4-haloisoxazoles Starting from Symmetric 1,2-
Diarylcyclopropanes
It is important to note that the last stage, halogenation of the
isoxazole ring, should be initiated only after full completion of
the previous nitrosation−oxidation processes (TLC control).
The question is that nitrosation of 1,2-diarylcyclopropanes is a
rate-limiting stage in these reaction sequences. The oxidation
of 4,5-dihydroisoxazole to the corresponding isoxazole, as well
as the oxidation of halide anions to the electrophilic species,
proceeds much more vigorously. As a result, the hasty addition
of tetramethylammonium halide into the reaction medium
leads to the foremost consumption of nitrosylsulfuric acid for
halide ion oxidation rather than cyclopropane nitrosation.
Thus, starting from the corresponding 1,2-diarylcyclopropanes
16−18, the full one-pot nitrosation−oxidation−halogenation
reaction sequence afforded direct access to the targeted
isoxazoles 1a−c, 2a−c, and 19a,c, respectively, in 70−93%
overall yields (Scheme 3), and the nitrosylsulfuric acid can be
viewed as a tandem nitrosation−oxidation process agent.
Scheme 3. One-Pot Synthesis of 3,5-Diaryl-4-haloisoxazoles
from 1,2-Diarylcyclopropanes
One of the routes for the construction of five-membered
N,O-heterocyclic scaffolds, isoxazolines, or isoxazoles is
nitrosation of cyclopropanes.22−25 Recently, we have shown
that nitrosylsulfuric acid can be successfully used in the
synthesis of 3,5-diarylisoxazoles from the corresponding 1,2-
diarylcyclopropanes.26,27 We envisioned the scenario depicted
in Scheme 2
Indeed, the portion-wise addition of 1.5 followed by 1 equiv
of nitrosylsulfuric acid in an hour or two to a solution of 1,2-
diarylcyclopropane in MeNO2 resulted in the sequential
formation of the corresponding 3,5-diaryl-4,5-dihydroisoxazole
followed by 3,5-diarylisoxazole that can be monitored by TLC.
Finally, the introduction of an additional portion of nitro-
sylsulfuric acid and tetramethylammonium halide into the
resulting mixture afforded the targeted 4-haloisoxazole.
The first results prompted our further investigations with a
variety of substances. A series of pyrazoles 20−22 was
halogenated under the standard conditions in uniformly
good yields of the corresponding 4-halopyrazoles 20a, 21a,b,
and 22a−c (Scheme 4).
Finally, we tested some other aromatic systems for their
ability toward halogenation under suggested conditions.
Compounds 23−30 depicted at Scheme 5 were obtained in
good yields (for details of the experiments, see Supporting
Information). Benzenes with electron-withdrawing groups,
namely, nitrobenzene, bromobenzene, and 4-nitrotoluene,
occur inactively and were recovered intact. Since for
C
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Although we did not specially investigate the mechanism of
halogenation when using the R4NHal/NOHSO4 system, we
can express some considerations on this issue based on the
literature and the facts at our disposal. As the common feature
of 1,2-azoles, SEAr reactions occur at the 4-position of the
isoxazole ring.28 The latest report on the electrophilic
halogenation of isoxazole confirms the following: treatment
of unsubstituted isoxazole with NIS/TFA under microwave
irradiation conditions (120 °C) afforded only 4-iodoisoxazole
in 70% yield.29 The specific rules of the orientation in the azole
series are determined by heteroatoms of two types in the azole
molecules. A reaction is directed preferentially to that position
of the heterocycle that is the least deactivated by the “pyridine”
nitrogen atom (the β-position relative to Npyrid).30 Our data on
the reactivity of substrates, depending on the electronic
properties of substituents in the aromatic/heteroaromatic
rings and the orientation of the substituents in halogenation
with the R4NHal/NOHSO4 system, also testify in favor of the
electrophilic substitution reaction. So the question is as
follows: what is an electrophilic particle “Hal+”, and how is it
formed?
Scheme 4. Halogenation of 3,5-Disubstituted Pyrazoles
Scheme 5
Early assumptions about the processes occurring during the
halogenation of isoxazoles were expressed in the works of
Sokolov et al., which successfully carried out bromination and
iodination of isoxazoles in the presence of an oxidizing agent
(HNO3 d = 1.5).31 It is known that nitrogen-containing
heterocycles form complexes of various compositions with
halogens, which are used for the halogenation of donor
aromatics, and in some cases, they are intermediates in
halogenation of the heterocycles their selves. An example is the
autohalogenation of pyridine.32 The same complexes are
known for the oxazole series.33 Sokolov et al. suggested that
isoxazole complexes with bromine or iodine (A) are
halogenating agents in the halogenation reactions.31 In the
absence of any additive (oxidants, catalysts), complexes of type
A carry out intermolecular electrophilic substitution.21 In their
opinion, the action of an oxidizing agent in the halogenation
reaction is apparently reduced to facilitating the appearance of
cation B from complex A by oxidation of the halide anion (eq
1).
mesitylene and p-xylene, bis-iodination products 24 and 25
were easily formed when the excess of an iodine surrogate was
used, we tried several monosubstituted five-membered hetero-
cycles with more than one C−H bond in the heteroring. In all
cases, except 2-thiophenecarbaldehyde, we obtained mono-
iodinated products 31−33 (Scheme 6).
The assumption that the halogenating agent appears to be a
complex cation B is confirmed by the absence of substitution
in aryl rings of arylated isoxazoles and is explained by the
additional deactivation of aromatic rings in the complex cation
B. It is obvious that the additional effect of a positively charged
halogen bound to nitrogen is quite large that, even with an
excess of the halogenating reagent, only 4-haloisoxazoles are
formed without any traces of the halogenation at benzene
rings.
Scheme 6
In 1988, Radner F. suggested a simple method for the
iodination of aromatic compounds, using I− as the iodine
source and O2 and catalytic amounts of NOBF4 as the
oxidant.34 In this work, the formation of “I+” was discussed in
terms of possible outer-sphere and inner-sphere electron-
transfer steps. Some data concerning the mechanism of direct
iodination of aromatic compounds are presented in the review
by Merkushev E., where it was emphasized that the existence of
D
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the iodine cation as a kinetically independent species is
possible only in highly acid media.35
Taking into account these considerations, we can suggest a
rational scheme of the transformations proceeding in the
reaction medium during the halogenation of aromatic
compounds by the R4NHal/NOHSO4 system (eqs 2−5).At
given in Table 2 demonstrate the high competitiveness of the
R4NHal/NOHSO4 system: the yields of the products are
usually comparable or superior to that obtained by the other
methods. Some of these methods suffer from the disadvantage
of the drastic conditions employed. Elevated temperatures and
strongly acidic media are used in reactions with N-
halosuccinimides. To achieve high yields in iodination, a
significant excess of NIS is required, which is rather an
expensive reagent. Using silver salts as a hydrogen iodide trap
also has some disadvantages, namely, the high cost of silver
salts and the loss of one equivalent of the halogenating reagent
in the form of silver halide. The use of the R4NHal/NOHSO4
system offers a number of advantages in terms of the reagent
availability, ease of handling, and reaction workup in
comparison to other methods. All reaction wastes are water-
soluble and meet the challenges of green chemistry.
the initial stage, we observe the oxidation of halide anions to
halogens accompanying by intense coloring of the solution (eq
2). The next step is the generation of effective electrophilic
species in which the nitrosonium cation can play the role of a
Lewis acid followed by the SEAr reaction with an aromatic
compound (eq 3). At this stage, in the case of isoxazoles, we do
not exclude the possibility of the transformation shown by eq
1. The final step is regeneration of Hal2 schematically
presented by eqs 4 and 5. In conclusion, we must note that,
in all cases of halogenation, the halogenating agent is a
complex cation that is in agreement with the high selectivity
and mild character of the R4NHal/NOHSO4 system. The key
role of NO+ is to promote the formation of some positive
halide species. This is consistent with the fact that chlorination
is more difficult than bromination, and the latter is more
difficult than iodination, which can be explained by the higher
oxidation potential of chlorine and bromine compared to the
potential of iodine.
CONCLUSIONS
■
We suggested a new convenient and versatile halogenating
system, R4NHal/NOHSO4, which opens a straightforward and
general access to halogenated 3,5-diaryl- and alkylarylisox-
azoles, pyrazoles, and electron-rich benzenes from the
corresponding scaffolds. The method offers a broad scope
for both halogens and aromatics and provides excellent
regioselectivity of the halogenation. The products can be
produced on a gram scale without chromatographic
purification. We also developed a three-step, one-pot protocol
for the synthesis of 3,5-diaryl-4-haloisoxazoles starting from
available 1,2-diarylcyclopropanes. The suggested sequence of
the reactions in which isoxazoline formation, followed by its
oxidation to isoxazole, and subsequent isoxazole halogenation
performed by sequential addition of the reagents, makes it
possible to reduce the number of the workup and purification
step. The most significant features of the one-pot synthesis of
3,5-diaryl-4-haloisoxazoles are mild conditions and high
productivity. Thus, using the dual nitrosating and oxidative
character of nitrosylsulfuric acid, we performed a multistep
process as a simple synthetic procedure.
Quoting Radner F., we want to say that “despite the many
uncertainties regarding the mechanism discussed above, the
synthetic value of the reaction is considerable.” Table 2
illustrates this statement.
The data on the yields of halogenated 3,5-diarylisoxazoles,
pyrazoles, and beyond obtained by this method and others
Table 2. Comparative Data on the Yields of Haloisoxazoles, Pyrazoles, and beyond Obtained by This Method and Others
comp
Hal. system
yield (%) Hal. system yield (%) ref
comp
Hal. system
yield (%)
Hal. system
NIS
yield (%) ref
a
1a
1b
1c
4a
4b
4c
6a
6b
6c
7a
7b
12a
12c
14b
15c
20a
21a
Me4NBr/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NBr/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NBr/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NBr/NOHSO4
Me4NI/NOHSO4
Me4NBr/NOHSO4
Me4NCl/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NBr/NOHSO4
Me4NBr/NOHSO4
89
87
87
88
86
92
89
85
92
72
66
98
85
91
96
95
95
NBS
80
85
99
86
59
88
71
94
75
b
11
17
11
17
17
17
38
39
11
40
41
17
17
11
42
43
43
21b
22b
23a
23b
23c
24
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NBr/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NI/NOHSO4
Me4NCl/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
Me4NI/NOHSO4
72
87
78
70
86
84
91
94
88
78
81
73
98
85
70
85
92
c
43
44
45
46
47
48
48
49
50
51
52
53
54
55
56
57
a
NIS
NCS
NBS
NIS
PhSSPh/NBS
I2/H2O2/HCl
NCS
35
97
60
53
78
62
75
83
86
72
95
94
76
90
d
NCS
NBS
I2/mCPBA
I2/mCPBA
d
25
26
a
ICl
c
NCS
27b
27c
28b
28c
29
30
31
33
I2/CF3COOAg
NaIO4/Cl2
KICl2
Cl2/AcOH
IBX/I2
NIS/TFA
NIS/TFA
I2/CAN
NIS
45
52
37
89
c
NBS
NCS
a
NIS
NBS
NBS
98
96
a
b
c
Indirect halogenation: haloisoxazoles were obtained via halogenative cyclization of alkynyl-O-methyl oximes. The yield is not specified. Indirect
d
halogenation. Indirect halogenation: compound was obtained via desulfonyloxyiodiation of the corresponding arenesulfonic acid.
E
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129.3, 127.5, 125.7, 124.9, 124.7, 124.6, 104.4; HRMS (ESI) m/z
[M+] calcd for C15H8Br2ClNO 410.8656, 412.8634, 414.8615,
416.8585; found 410.8664, 412.8639, 414.8622, 416.8587.
EXPERIMENTAL SECTION
■
General Information. The 1H and 13C NMR spectra were
recorded on Bruker Avance 400 and Agilent spectrometers with
working frequencies of 400.13 and 100.61 MHz in CDCl3 with TMS
as an internal standard. The mass spectra were registered on a
Finnigan MAT SSQ 7000 GC−MS instrument equipped with a 25 m
quartz capillary OV-1 column in the electron-impact ionization mode
at an ionization energy of 70 eV with temperature programming from
70 (2 min) to 280 °C (10 min) at a rate of 20 K min−1. Electrospray
ionization (ESI) high-resolution mass spectra were recorded on a
Bruker microTOF II instrument (direct input). The melting points
were measured in a block in an open capillary.
4-Bromo-3-(4-bromophenyl)-5-(4-methoxyphenyl)isoxazole
1
(3a): 90 mg (73% yield), colorless crystals; mp 138 °C; H NMR
(CDCl3, 400 MHz) δ 8.02 (d, 2H, J = 8.8 Hz), 7.74 (d, 2H, J = 8.3
Hz), 7.64 (d, 2H, J = 8.3 Hz), 7.03 (d, 2H, J = 8.8 Hz), 3.88 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 161.4, 161.1, 131.9,
130.1, 128.7, 126.9, 124.7, 119.2, 114.3, 87.8, 55.5; GC−MS (EI, 70
eV, m/z (Irel (%)) cluster 407 (10), 409 (17), 411 (9) [M+]; cluster
300 (3), 302 (4) [M − Br − CO]+; 249 (10) [M − 2Br]+; 135 (100)
[MeOC6H4CO]+; 107 (12) [MeOC6H4]+; 77 (15) [Ph]+; 76 (9)
[C6H4]+. Calcd for C16H11Br2NO2, %: C, 46.98; H, 2.71; N, 3.42.
Found, %: C, 46.93; H, 2.67; N, 3.45.
3,5-Diarylisoxazoles 1−8, 12, and 15 were obtained according to
well-known experimental procedures.36 Isoxazoles 9−11 and 14 as
well as cyclopropane 18 were kindly provided by L. G. Saginova
(M.V. Lomonosov Moscow State University). trans-1,2-Bis(4-
bromophenyl)cyclopropane 17 was obtained by the reaction of
trans-1,2-diphenylcyclopropane with NBS according to the LaLonde
procedure.37 Pyrazoles 20−22 were kindly provided by L. A.
Sviridova (M.V. Lomonosov Moscow State University). Other initials
were commercially available.
3-(4-Bromophenyl)-4-iodo-5-(4-methoxyphenyl)isoxazole (3b):
1
110 mg (80% yield), cream crystalline solid; mp 142 °C; H NMR
(CDCl3, 400 MHz) δ 8.02 (d, 2H, J = 8.6 Hz), 7.65 (m, 4H), 7.03 (d,
2H, J = 8.6 Hz), 3.88 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
169.2, 163.7, 161.5, 131.8, 130.5, 129.4, 127.8, 124.6, 119.6, 114.2,
55.5, 54.3; GC−MS (EI, 70 eV, m/z (Irel (%)) cluster 455 (16), 457
(14) [M+]; 249 (8) [M − Br − I]+; 135 (100) [MeOC6H4CO]+; 107
(10) [MeOC6H4]+; 77 (12) [Ph]+. Calcd for C16H11BrINO2, %: C,
42.14; H, 2.43; N, 3.07. Found, %: C, 42.08; H, 2.37; N, 3.05.
3-(4-Bromophenyl)-4-chloro-5-(4-methoxyphenyl)isoxazole (3c):
Halogenation of 3,5-diarylisoxazoles 1−12, 14, and 15,
Pyrasoles 20−22, and beyond (General Procedure). A thoroughly
dried 50 mL round-bottom flask equipped with a tightly fitted stopper
and a magnetic rod was sequentially charged with crystalline
nitrosylsulfuric acid, 10 mL of dry nitromethane, tetramethylammo-
nium salt, and 1 mmol of arene/hetarene, and the resultant mixture
was stirred on a magnetic stirrer (for experimental details, see Tables
S1−S3). The reaction progress was monitored by TLC. After
completion of the reaction, the resultant mixture was quenched
with 10% NaHCO3 aqueous solution (10 mL), and organic
substances were extracted with CH2Cl2 (3 × 15 mL). Combined
organic layers were washed with 10% Na2SO3 aqueous solution (10
mL) and then water (15 mL) and dried over Na2SO4. The solvent was
evaporated in vacuo to give the crude product, which, if necessary,
was purified by recrystallization from ethanol for solid compounds or
by flash chromatography for liquid compounds.
1
75 mg (68% yield); white amorphous solid; mp 118 °C; H NMR
(CDCl3, 400 MHz) δ 7.99 (d, 2H, J = 8.7 Hz), 7.77 (d, 2H, J = 8.4
Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.7 Hz), 3.87 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 164.5, 161.4, 159.7, 132.0,
129.7, 128.2, 126.5, 124.8, 118.9, 114.4, 102.9, 55.4. Calcd for
C16H11BrClNO2, %: C, 52.70; H, 3.04; N, 3.84. Found, %: C, 52.85;
H, 3.17; N, 3.75.
4-Bromo-5-(4-bromophenyl)-3-phenylisoxazole (4a):17 167 mg
(88% yield), white crystalline solid; mp 118−119 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.96 (d, 2H, J = 8.6 Hz), 7.84−7.88 (m, 2H),
7.65 (d, 2H, J = 8.6 Hz), 7.49−7.56 (m, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 164.8, 162.2, 132.2, 130.3, 128.7, 128.6, 128.4, 127.6,
125.6, 125.3, 90.0; GC−MS (EI, 70 eV, m/z (Irel (%)) cluster 377
(11), 379 (22), 381 (11) [M+]; cluster 298 (14), 300 (14) [M −
Br]+; cluster 270 (12), 272 (11) [M − CO − Br]+; cluster 258 (16),
260 (18); 219 (19) [M − 2Br]+; cluster 183 (100), 185 (90)
[BrC6H4CO]+; cluster 155 (69), 157 (64) [BrC6H4]+, 77 (59) [Ph]+,
76 (72) [C6H4]+, 75 (60).
4-Bromo-3,5-diphenylisoxazole (1a):11 133 mg (89% yield),
1
white crystalline solid; mp 130 °C; H NMR (CDCl3, 400 MHz) δ
8.08−8.13 (m, 2H), 7.88−7.92 (m, 2H), 7.49−7.56 (m, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 165.8, 162.1, 130.7, 130.2,
128.9, 128.7, 128.6, 127.9, 127.1, 126.8, 89.6.
5-(4-Bromophenyl)-4-iodo-3-phenylisoxazole (4b):17 128 mg
(86% yield), white amorphous solid; mp 151−152 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.96 (d, 2H, J = 8.6 Hz), 7.77−7.81 (m, 2H),
7.66 (d, 2H, J = 8.6 Hz), 7.50−7.55 (m, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 167.9, 164.9, 132.1, 130.2, 129.2, 129.0, 128.6, 128.5,
126.1, 125.3, 56.6; HRMS (ESI) m/z [M + H]+ calcd for
C15H10BrINO 425.8985, 427.8964; found 425.9017, 427.8976.
5-(4-Bromophenyl)-4-chloro-3-phenylisoxazole (4c):17 154 mg
(92% yield), white crystalline solid; mp 110−111 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.92 (d, 2H, J = 8.6 Hz), 7.88 (m, 2H), 7.65 (d,
2H, J = 8.6 Hz), 7.49−7.55 (m, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.7, 160.4, 131.8, 130.0, 128.4, 127.8, 127.5, 126.8, 124.9,
124.7, 104.6.
4-Iodo-3,5-diphenylisoxazole (1b):11 75 mg (87% yield), yellow-
ish solid; mp 172 °C; 1H NMR (CDCl3, 400 MHz) δ 8.06−8.12 (m,
2H), 7.80−7.84 (m, 2H), 7.50−7.57 (m, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 169.0, 164.8, 130.8, 130.1, 129.1, 128.8, 128.7, 128.6,
127.8, 127.3, 56.2.
4-Chloro-3,5-diphenylisoxazole (1c):11 66 mg (87% yield), white
solid; mp 84 °C; 1H NMR (CDCl3, 400 MHz) δ 8.07−8.10 (m, 2H),
7.88−7.96 (m, 2H), 7.49−7.57 (m, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 164.1, 160.8, 130.6, 130.3, 128.9, 128.8, 128.3, 127.4,
126.57, 126.52, 104.6.
4-Bromo-3,5-bis(4-bromophenyl)isoxazole (2a): 118 mg (98%
yield), white crystalline solid; mp 180°C; 1H NMR (CDCl3, 400
MHz) δ 7.97 (d, 2H, J = 8.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.65−7.72
(m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.1, 161.3, 132.2,
132.0, 130.0, 128.4, 126.5, 125.4, 124.9, 89.6. One signal is
overlapped. Calcd for C15H8Br3NO, %: C, 39.34; H, 1.76; N, 3.06.
Found, %: C, 39.46; H, 1.84; N, 3.15.
3,5-Bis(4-bromophenyl)-4-iodoisoxazole (2b): 140 mg (70%
yield), yellowish crystalline solid; mp 151 °C; 1H NMR (CDCl3,
400 MHz) δ 7.94 (d, 2H, J = 8.6 Hz), 7.66 (m, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 168.2, 164.0, 132.1, 131.9, 130.5, 129.1, 127.4,
125.9, 125.5, 124.9, 56.2. Calcd for C15H8Br2INO, %: C, 35.68; H,
1.60; N, 2.77. Found, %: C, 35.67; H, 1.63; N, 2.77.
4-Bromo-3-(3-bromo-4-methylphenyl)-5-phenylisoxazole (5a):
1
225 mg (90% yield), white crystalline solid; mp 110 °C; H NMR
(CDCl3, 400 MHz) δ 8.05−8.11 (m, 3H), 7.73 (dd, 1H, J = 1.6, J =
7.9 Hz), 7.51−7.57 (m, 3H), 7.38 (d, 1H, J = 7.9 Hz), 2.49 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 160.7, 140.3, 132.2,
131.0, 130.8, 128.9, 127.4, 127.1, 126.6, 125.1, 89.3, 23.0. One signal
is overlapped. GC−MS (EI, 70 eV, m/z (Irel (%)) cluster 391 (9), 393
(16), 395 (8) [M+]; cluster 284 (5), 286 (5) [M+ − Br − CO];
cluster 272 (4), 274 (4); 233 (21) [M − 2Br]+; 105(100) [PhCO]+;
77(41) [C6H5]+; 51 (5) [C4H3]+. Calcd for C16H11Br2NO, %: C,
48.89; H, 2.82. Found, %: C, 49.04; H, 3.20.
3,5-Bis(4-bromophenyl)-4-chloroisoxazole (2c): 155 mg (92%
3-(3-Bromo-4-methylphenyl)-4-iodo-5-phenylisoxazole (5b): 202
mg (92% yield), pale yellow solid; mp 122 °C; 1H NMR (CDCl3, 400
MHz) δ 8.04−8.11 (m, 2H), 8.01 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz),
7.48−7.59 (m, 3H), 7.38 (d, 1H, J = 8.5 Hz), 2.49 (s, 3H); 13C{1H}
1
yield), white crystalline solid; mp 122 °C; H NMR (CDCl3, 400
MHz) δ 7.93 (d, 2H, J = 8.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.67 (m,
4H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.0, 159.5, 131.9, 131.7,
F
https://dx.doi.org/10.1021/acs.joc.0c02106
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
NMR (101 MHz, CDCl3) δ 169.1, 163.3, 140.0, 132.6, 130.81, 130.8,
128.8, 127.9, 127.8, 127.7, 127.1, 124.9, 55.8, 23.0; HRMS (ESI) m/z
[M + H]+ calcd for C16H12BrINO 439.9141, 441.9122; found
439.9128, 441.9114.
C15H9IN2O3, %: C, 45.94; H, 2.31; N, 7.14. Found, %: C, 46.07; H,
2.04; N, 7.13.
4-Bromo-3-(4-nitrophenyl)-5-phenylisoxazole (9a): 60 mg (85%
1
yield), white crystalline solid; mp 157 °C; H NMR (CDCl3, 400
3-(3-Bromo-4-methylphenyl)-4-chloro-5-phenylisoxazole (5c):
MHz) δ 8.39 (d, 2H, J = 8.7 Hz), 8.08−8.12 (m, 4H), 7.56−7.58 (m,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 160.3, 148.8, 134.1,
131.1, 129.6, 129.0, 127.1, 126.3, 123.9, 89.1; GC−MS (EI, 70 eV, m/
z (Irel (%)) 266 (52) [M+], 105 (100) [PhCO]+. Calcd for
C15H9BrN2O3, %: C, 52.20; H, 2.63; N, 8.12. Found, %: C, 51.95;
H, 3.07; N, 8.15.
1
103 mg (98% yield), white solid; mp 114 °C; H NMR (CDCl3,
400 MHz) δ 8.10 (s, 1H), 8.03−8.08 (m, 2H), 7.76 (d, 1H, J = 7.9
Hz), 7.53 (m, 3H), 7.38 (d, 1H, J = 7.9 Hz), 2.48 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 163.9, 159.0, 139.9, 131.4, 130.6, 130.3,
128.5, 126.6, 126.2, 126.1, 125.9, 124.8, 104.0, 22.6; GC−MS (EI, 70
eV, m/z (Irel (%)) cluster 347 (12), 349 (19), 351 (3) [M+]; cluster
312 (2), 314 (2) [M+− Cl]; cluster 272 (5), 274 (5); cluster 240
(16), 242 (5) [M+ − Br − CO]; 233 (14) [M+ − Cl − Br]; 105(100)
[PhCO]+; 89 (11) [C7H5]+; 77(43) [C6H5]+. Calcd for
C16H11BrClNO, %: C, 55.12; H, 3.18. Found, %: C, 55.74; H, 3.43.
4-Bromo-3-(4-chlorophenyl)-5-phenylisoxazole (6a):38 175 mg
4-Iodo-3-(4-nitrophenyl)-5-phenylisoxazole (9b): 35 mg (88%
1
yield), cream crystals; mp 139 °C; H NMR (CDCl3, 400 MHz) δ
8.39 (d, 2H, J = 8.9 Hz), 8.04−8.13 (m, 2H), 8.02 (d, 2H, J = 8.9
Hz), 7.50−7.60 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.5,
162.6, 148.4, 134.6, 130.7, 129.7, 128.5, 127.4, 126.3, 123.4, 54.7;
HRMS (ESI) m/z [M + H]+ calcd for C15H10IN2O3 392.9731, found
392.9734.
1
(89% yield), colorless crystals; mp 126−127 °C; H NMR (CDCl3,
400 MHz) δ 8.08 (m, 2H), 7.83 (d, 2H, J = 8.4 Hz), 7.53 (m, 3H),
7.50 (d, 2H, J = 8.4 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1,
161.1, 136.5, 130.8, 129.9, 129.0, 128.9, 127.1, 126.6, 126.3, 89.3.
3-(4-Chlorophenyl)-4-iodo-5-phenylisoxazole (6b):39 190 mg
(85% yield), white crystals; mp 165 °C; 1H NMR (CDCl3, 400
MHz) δ 8.09 (m, 2H), 7.76 (d, 2H, J = 8.1 Hz), 7.51 (m, 5H);
13C{1H} NMR (101 MHz, CDCl3) δ 169.3, 163.8, 136.4, 130.9,
130.3, 128.9, 128.8, 127.8, 127.2, 127.1, 55.8; GC−MS (EI, 70 eV, m/
z (Irel (%)) cluster 381 (4), 383 (1) [M+]; cluster 137 (3), 139 (1)
[ClC6H4CN]+; 114 (5) [M − I − PhCO − Cl]+; 105 (100)
[PhCO]+; 77 (54) [Ph]+.
4-Bromo-3-(2-methylphenyl)-5-phenylisoxazole (10a): 130 mg
(98% yield), purified by flash chromatography (eluent, ethyl acetate/
light petroleum ether = 1:10), yellow oil; 1H NMR (CDCl3, 400
MHz) δ 8.14−8.17 (m, 2H), 7.54−7.58 (m, 3H), 7.32−7.46 (m, 4H),
2.39 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.9, 163.9,
137.6, 130.7, 130.5, 130.1, 130.0, 128.9, 127.2, 126.9, 126.8, 125.8,
91.3, 20.0. Calcd for C16H12BrNO, %: C, 61.17; H, 3.85; N, 4.46.
Found, %: C, 61.52; H, 4.09; N, 4.56.
4-Bromo-3-(2-methoxy-5-chlorophenyl)-5-phenylisoxazole
(11a): 126 mg (99% yield), purified by flash chromatography (eluent,
1
ethyl acetate/light petroleum ether = 1:10), yellowish oil; H NMR
4-Chloro-3-(4-chlorophenyl)-5-phenylisoxazole (6c):11 157 mg
(92% yield), white crystalline solid; mp 95 °C; 1H NMR (CDCl3, 400
MHz) δ 8.06 (m, 2H), 7.86 (d, 2H, J = 8.4 Hz), 7.52−7.58 (m, 3H),
7.50 (d, 2H, J = 8.4 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4,
159.8, 136.6, 130.8, 129.5, 129.1, 129.0, 126.6, 126.3, 125.9, 104.4;
GC−MS (EI, 70 eV, m/z (Irel (%)) cluster 289 (6), 291 (4), 293
(0.8) [M+]; cluster 254 (3), 256 (1) [M − Cl]+; cluster 214 (3), 216
(1); cluster 137 (3), 139 (1) [ClC6H4CN]+; 105 (100) [PhCO]+; 77
(68) [Ph]+.
(CDCl3, 400 MHz) δ 8.11−8.14 (m, 2H), 7.54−7.55 (m, 3H), 7.47
(dd, 1H, J = 8.8, J = 2.7 Hz), 7.44 (d, 1H, J = 2.7 Hz), 6.99 (d, 1H, J =
8.8 Hz), 3.88 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.6,
160.8, 155.8, 131.0, 130.6, 130.2, 128.4, 126.5, 126.3, 125.1, 117.9,
112.1, 91.3, 55.6. Calcd for C16H11BrClNO2, %: C, 52.70; H, 3.04; N,
3.84. Found, %: C, 52.48; H, 3.35; N, 3.93.
4-Bromo-5-(4-methoxyphenyl)-3-phenylisoxazole (12a):17 193
1
mg (98% yield), white solid; mp 140 °C; H NMR (CDCl3, 400
MHz) δ 8.06 (d, 2H, J = 8.7 Hz) 7.87 (m, 2H), 7.53 (m, 3H), 7.05
(d, 2H, J = 8.7 Hz), 3.89 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 165.4, 161.6, 160.9, 129.7, 128.3, 128.2, 128.17, 127.6, 119.0, 113.8,
87.7, 55.0.
4-Bromo-3,5-bis(4-methoxyphenyl)isoxazole (7a):40 129 mg
1
(72% yield), white solid; mp 128 °C; H NMR (CDCl3, 400 MHz)
δ 8.02 (d, 2H, J = 8.8 Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.02 (d, 4H, J =
8.8 Hz), 3.86 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.6,
161.6, 161.3, 161.0, 129.9, 128.6, 120.3, 119.4, 114.2, 114.1, 88.1,
55.42, 55.36.
4-Chloro-5-(4-methoxyphenyl)-3-phenylisoxazole (12c):17 24 mg
(85% yield), white solid; mp 101 °C; 1H NMR (CDCl3, 400 MHz) δ
8.03 (d, 2H, J = 8.0 Hz), 7.83−7.95 (m, 2H), 7.43−7.57 (m, 3H),
7.05 (d, 2H, J = 8.0 Hz), 3.89 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 163.7, 160.9, 160.2, 129.8, 128.3, 127.83, 127.8, 127.2,
118.8, 113.9, 102.7, 55.0.
4-Iodo-3,5-bis(4-methoxyphenyl)isoxazole (7b):41 134 mg (66%
1
yield), yellowish solid; mp 163 °C; H NMR (CDCl3, 400 MHz) δ
8.04 (d, 2H, J = 8.3 Hz), 7.75 (d, 2H, J = 8.3 Hz), 7.04 (m, 4H), 3.89
(s, 3H), 3.88 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.8,
164.2, 161.3, 161.0, 130.4, 129.4, 121.1, 119.9, 114.1, 114.0, 55.44,
55.37, 54.8.
4-Bromo-5-(3-bromo-4-methoxyphenyl)-3-phenylisoxazole (13):
158 mg (97% yield), colorless crystals; mp 153 °C; 1H NMR (CDCl3,
400 MHz) δ 8.33 (d, 1H, J = 2.1), 8.06 (dd, 1H, J = 8.6, J = 2.1 Hz),
7.87 (m, 2H), 7.52−7.56 (m, 3H), 7.06 (d, 1H, J = 8.6 Hz), 4.00 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2, 162.0, 157.4, 131.7,
130.1, 128.6, 128.4, 127.6, 127.5, 120.4, 112.0, 111.6, 88.7, 56.3.
Calcd for C16H11Br2NO2, %: C, 46.98; H, 2.71; N, 3.42. Found, %: C,
47.04; H, 3.10; N, 3.64.
4-Chloro-3,5-bis(4-methoxyphenyl)isoxazole (7c): 138 mg (88%
1
yield), white crystalline solid; mp 123 °C; H NMR (CDCl3, 400
MHz) δ 8.00 (d, 2H, J = 8.8 Hz), 7.85 (d, 2H, J = 8.8 Hz), 7.03 (d,
4H, J = 8.8 Hz), 3.87 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
163.9, 161.2, 161.1, 160.2, 129.6, 128.2, 119.9, 119.2, 114.3, 114.2,
103.0, 55.41, 55.36. Calcd for C17H14ClNO3, %: C, 64.67; H, 4.47; N,
4.44. Found, %: C, 64.35; H, 4.42; N, 4.51.
4-Iodo-3-methyl-5-phenylisoxazole (14b):11 78 mg (91% yield),
purified by flash chromatography (eluent, ethyl acetate/light
1
4-Bromo-5-(3-nitrophenyl)-3-phenylisoxazole (8a): 117 mg (86%
petroleum ether = 1:10), yellow oil; H NMR (CDCl3, 400 MHz)
1
δ 8.03 (m, 2H), 7.48 (m, 3H), 2.35 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 167.4, 163.0, 130.6, 128.7, 127.3, 127.2, 57.9, 12.7.
4-Iodo-3-(4-methylphenyl)-5-phenylisoxazole (15b): 145 mg
(95% yield), cream crystalline solid; mp 92 °C; 1H NMR (400
yield), white amorphous solid; mp 119−120 °C; H NMR (CDCl3,
400 MHz) δ 9.02 (br s, 1H), 8.43 (d, 1H, J = 8.0 Hz), 8.38 (d, 1H, J =
8.0 Hz), 7.87 (m, 2H), 7.76 (t, 1H, J = 8.0 Hz), 7.55 (m, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 162.0, 148.1, 132.0,
130.1, 129.8, 128.4, 128.2, 127.8, 126.8, 124.7, 121.4, 91.0; HRMS
(ESI) m/z [M + H]+ calcd for C15H10BrN2O3 344.9869, 346.9849;
found 344.9869, 346.9854.
1
MHz, CDCl3) δ H NMR (CDCl3, 400 MHz) δ 8.09 (m, 2H), 7.71
(d, 2H, J = 7.9 Hz), 7.49−7.58 (m, 3H), 7.34 (d, 2H, J = 7.9 Hz),
2.45 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 164.7,
140.2, 130.7, 129.3, 128.9, 128.7, 127.8, 127.4, 125.8, 56.2, 21.5;
HRMS (ESI) m/z [M + H]+ calcd for C16H13INO 362.0036, found
362.0040.
4-Iodo-5-(3-nitrophenyl)-3-phenylisoxazole (8b): 245 mg (98%
1
yield), cream amorphous solid; mp 144−145 °C; H NMR (CDCl3,
400 MHz) δ 9.02 (s, 1H), 8.42 (d, 1H, J = 8.1 Hz), 8.37 (d, 1H, J =
8.1 Hz), 7.78 (m, 2H), 7.75 (t, 1H, J = 8.1 Hz), 7.51−7.56 (m, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 165.8, 164.7, 147.9, 132.8,
130.0, 129.7, 128.6, 128.31, 128.3, 127.7, 124.8, 122.2, 57.7. Calcd for
4-Chloro-3-(4-methylphenyl)-5-phenylisoxazole (15c):42 55 mg
1
(96% yield), white amorphous solid; mp 104 °C; H NMR (CDCl3,
400 MHz) δ 8.04−8.12 (m, 2H), 7.81 (d, 2H, J = 6.5 Hz), 7.49−7.59
G
https://dx.doi.org/10.1021/acs.joc.0c02106
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(m, 3H), 7.34 (d, 2H, J = 6.5 Hz), 2.45 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 163.6, 160.3, 140.1, 130.1, 129.1, 128.5, 127.7, 126.1,
124.1, 104.2, 21.1. One signal is overlapped.
7.07 (d, 1H, J = 7.7 Hz), 2.42 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 138.9, 137.7, 136.8, 129.0, 128.6, 100.7, 27.2,
19.9
4-Bromo-3,5-dimethyl-1H-pyrazole (20a):43 173 mg (95% yield),
1-Iodo-4-methoxybenzene (27b):50 190 mg (88% yield), cream
solid; mp 50−52 °C; 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J =
8.7 Hz), 6.69 (d, 2H, J = 8.7 Hz), 3.77 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 159.0, 137.8, 116.0, 82.3, 54.9.
1
colorless crystals; mp 123 °C; H NMR (CDCl3, 400 MHz) δ 12.5
(br s, 1H), 2.25 (s); 13C{1H} NMR (101 MHz, CDCl3) δ 142.7, 94.2,
11.2.
1-Chloro-4-methoxybenzene (27c):51 103 mg (78% yield),
purified by flash chromatography (eluent, ethyl acetate/light
petroleum ether = 1:20), colorless liquid; 1H NMR (CDCl3, 400
MHz) δ 7.24 (d, 2H, J = 9.0 Hz), 6.83 (d, 2H, J = 9.0 Hz), 3.79 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.8, 128.9, 125.1, 114.8,
55.1.
4-Bromo-3,5-dimethyl-1-phenyl-1H-pyrazole (21a):43 145 mg
(95% yield), purified by flash chromatography (eluent, ethyl
acetate/light petroleum ether = 1:10); yellow oil: 1H NMR
(CDCl3, 400 MHz) δ 7.30−7.48 (m, 5H), 2.29 (s, 3H), 2.28 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ, 147.5, 139.8, 137.4, 129.2,
127.8, 124.6, 96.4, 12.4, 11.8.
5-Iodoisatine (28b):52 117 mg (81% yield), red solid; mp 274 °C;
1H NMR (DMSO-d6, 400 MHz) δ 11.09 (s, 1H), 7.86 (dd, 1H, J =
8.2, J = 1.6 Hz), 7.74 (d, 1H, J = 1.6 Hz), 6.73 (d, 1H, J = 8.2 Hz);
13C{1H} NMR (101 MHz, DMSO-d6) δ 183.1, 158.7, 150.0, 145.8,
132.4, 120.0, 114.6, 85.4.
4-Iodo-3,5-dimethyl-1-phenyl-1H-pyrazole (21b):43 130 mg
(72% yield), purified by flash chromatography (eluent, ethyl
1
acetate/light petroleum ether = 1:10), yellow oil; H NMR (CDCl3,
400 MHz) δ 7.31−7.48 (m, 5H), 2.30 (s, 3H), 2.29 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.7, 140.8, 139.9, 129.2, 127.9, 124.8,
65.5, 14.2, 13.5; GC−MS (EI, 70 eV, m/z (Irel (%)) 298 (50) [M+];
297 (16) [M − H]+; 170 (18) [M − I − H]+; 130 (19); 127 (14);
118 (17); 77 (100) [Ph+].
5-Chloroisatine (28c):53 45 mg (73% yield), orange solid; mp 256
°C; 1H NMR (DMSO-d6, 400 MHz) δ 11.13 (s, 1H), 7.59 (dd, 1H, J
= 8.3, J = 2.2 Hz), 7.52 (d, 1H, J = 2.2 Hz), 6.91 (d, 1H, J = 8.3 Hz);
13C{1H} NMR (101 MHz, DMSO-d6) δ 183.4, 159.2, 149.3, 137.3,
126.8, 124.1, 119.1, 113.9.
1-Benzyl-4-bromo-3,5-diphenyl-1H-pyrazole (22a): 165 mg (85%
1
yield), white crystalline solid; mp 112 °C; H NMR (CDCl3, 400
4,4′-Diiododiphenyl ether (29);54 170 mg (98% yield), cream
crystalline solid; mp 140 °C; 1H NMR (CDCl3, 400 MHz) δ 7.63 (d,
4H, J = 8.9 Hz), 6.77 (d, 4H, J = 8.9 Hz); 13C{1H} NMR (101 MHz,
CDCl3) δ 156.3, 138.4, 120.7, 86.2.
MHz) δ 8.02 (m, 2H), 7.46−7.54 (m, 5H), 7.42 (m, 1H), 7.37 (m,
2H), 7.26−7.33 (m, 3H), 7.10 (m, 2H), 5.35 (s, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 148.5, 143.3, 136.9, 132.3, 130.1, 129.4, 128.8,
128.7, 128.6, 128.4, 128.2, 127.9, 127.7, 127.1, 92.9, 54.4. Calcd for
C22H17BrN2, %: C, 67.88; H, 4.40; N, 7.20. Found, %: C, 68.14; H,
4.34; N, 7.52.
1-Iodo-2,4-dimethylbenzene (30):55 93 mg (85% yield), purified
by flash chromatography (eluent, ethyl acetate/light petroleum ether
= 1:20), yellowish oil; 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 1H, J
= 8.0 Hz), 7.09 (s, 1H), 6.72 (d, 1H, J = 8.0 Hz), 2.42 (s, 3H), 2.30
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 140.8, 138.3, 137.7,
130.4, 128.0, 96.7, 27.5, 20.5.
1-Benzyl-4-iodo-3,5-diphenyl-1H-pyrazole (22b):44 190 mg (87%
1
yield), yellow crystalline solid; mp 120 °C; H NMR (CDCl3, 400
MHz) δ 7.99 (m, 2H), 7.42−7.53 (m, 6H), 7.35 (m, 2H), 7.26−7.32
(m, 3H), 7.10 (m, 2H), 5.36 (s, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 151.8, 146.8, 136.9, 133.1, 130.4, 130.0, 129.5, 128.73,
128.65, 128.5, 128.34, 128.30, 127.8, 127.2, 61.3, 54.6.
3-(4-Chlorophenyl)-4-iodoisoxazole (31):56 purified by flash
chromatography (eluent, ethyl acetate/light petroleum ether =
1:10), 37 mg (70%), white crystals; mp 99−100 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.48 (s, 1H), 7.78 (d, 2H, J = 8.6 Hz), 7.48 (d,
2H, J = 8.6 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 162.4, 160.8,
136.1, 129.5, 129.3, 128.6, 57.4.
1-Benzyl-4-chloro-3,5-diphenyl-1H-pyrazole (22c): 90 mg (86%
1
yield), white amorphous solid; mp 104 °C; H NMR (CDCl3, 400
MHz) δ 8.03 (m, 2H), 7.46−7.53 (m, 5H), 7.42 (m, 1H), 7.36−7.40
(m, 2H), 7.26−7.34 (m, 3H), 7.11 (m, 2H), 5.34 (s, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 146.5, 141.1, 136.5, 131.5, 129.5, 129.0,
128.3, 128.2, 128.0, 127.7, 127.3, 127.1, 126.6, 106.7, 53.8. One signal
is overlapped. GC−MS (EI, 70 eV, m/z (Irel (%)) cluster 344 (70),
346 (23) [M+]; cluster 343 (56), 345 (19) [M − H]+; cluster 267
(40), 269 (13) [M − Ph]+; 189 (22), 91 (100). Calcd for
C22H17ClN2, %: C, 76.63; H, 4.97; N, 8.12. Found, %: C, 76.45; H,
4.80; N, 8.24.
4-Iodo-5-(4-methylphenyl)ioxazole (32): purified by flash chro-
matography (eluent, ethyl acetate/light petroleum ether = 1:10), 40
1
mg (75%), white crystals; mp 105−106 °C; H NMR (CDCl3, 400
MHz) δ 8.27 (s, 1H), 7.94 (d, 2H, J = 8.2 Hz), 7.31 (d, 2H, J = 8.2
Hz), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 156.4,
140.7, 129.1, 126.9, 123.6, 51.0, 21.2; HRMS (ESI) m/z [M + H]+
calcd for C10H9INO 285.9723, found 285.9719.
2-Bromo-1,3,5-trimethylbenzene (23a):45 233 mg (78% yield),
purified by flash chromatography (eluent, ethyl acetate/light
petroleum ether = 1:20), colorless liquid; 1H NMR (CDCl3, 400
MHz) δ 6.91 (s, 2H), 2.39 (s, 6H), 2.26 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 137.9, 136.3, 129.1, 124.2, 23.7, 20.7.
4-Iodo-5-methyl-1H-pyrazole (33):57 647 mg (85%), yellowish
solid; mp 110 °C; 1H NMR (CDCl3, 400 MHz) δ 11.41 (s, 1H), 7.55
(s, 1H), 2.33 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.9,
140.1, 59.3, 12.0.
3,4-Diiodothiophen-2-ylcarbaldehyde (34): 171 mg (88% yield),
yellowish crystalline solid; mp 145 °C; 1H NMR (CDCl3, 400 MHz)
δ 9.75 (s, 1H), 7.53 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
180.3, 150.3, 143.2, 98.0, 95.0; GC−MS (EI, 70 eV, m/z (Irel (%))
364 (100) [M+], 363 (58) [M − H]+, 208 (17) [M − I − CHO]+,
127 (16) [I+], 81 (25) [C4HS]+. Calcd for C5H2I2OS, %: C, 16.50; H,
0.55. Found, %: C, 16.53; H, 0.57.
Gram-Scale Procedure for Iodination of 3,5-Diarylisoxazoles. A
thoroughly dried 250 mL round-bottom flask equipped with a tightly
fitted stopper and a magnetic rod was sequentially charged with 4.5 g
(0.035 mol) of crystalline nitrosylsulfuric acid, 100 mL of dry
nitromethane, 2.5 g (0.012 mol) of tetramethylammonium iodide,
and 2.21 g (0.01 mol) of isoxazole 1, and the resultant mixture was
stirred on a magnetic stirrer at room temperature for 1−2 h. Over this
period of time, a precipitate appeared in the flask. Then the flask was
placed into a water bath, and the reaction mixture was heated at 55−
60 °C for 15−60 min to complete the reaction (monitoring by TLC).
After completion of the reaction, the resultant mixture was
sequentially shaken with NaHCO3 and Na2SO3 aqueous solutions,
the organic layer was separated and evaporated in vacuo to regenerate
2-Iodo-1,3,5-trimethylbenzene (23b):46 72 mg (70% yield),
1
colorless amorphous solid; mp 28−30 °C; H NMR (CDCl3, 400
MHz) δ 6.90 (s, 2H), 2.45 (s, 6H), 2.25 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 141.3, 136.9, 127.6, 103.9, 29.1, 20.3.
2-Chloro-1,3,5-trimethylbenzene (23c):47 66 mg (86% yield),
purified by flash chromatography (eluent, ethyl acetate/light
petroleum ether = 1:20), colorless liquid; 1H NMR (CDCl3, 400
MHz) δ 6.93 (s, 2H), 2.38 (s, 6H), 2.29 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 135.4, 135.1, 133.7, 128.8, 20.3, 20.2.
2,4-Diiodo-1,3,5-trimethylbenzene (24):48 130 mg (84% yield),
colorless crystals; mp 82 °C; 1H NMR (CDCl3, 400 MHz) δ 6.99 (s,
1H), 2.93 (s, 3H), 2.42 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
143.0, 141.4, 127.5, 102.8, 37.1, 29.6.
1,4-Diiodo-2,5-dimethylbenzene (25):48 306 mg (91% yield),
white solid; mp 101 °C; 1H NMR (CDCl3, 400 MHz) δ 7.64 (s, 2H),
2.34 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 140.2, 138.8,
100.3, 26.6.
2-Iodo-1,4-dimethylbenzene (26):49 727 mg (94%), yellow oil; 1H
NMR (CDCl3, 400 MHz) δ 7.68 (s, 1H), 7.14 (d, 1H, J = 7.7 Hz),
H
https://dx.doi.org/10.1021/acs.joc.0c02106
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
nitromethane, and the residue was dissolved in CH2Cl2. The water
layers were treated with CH2Cl2. Combined organic fractions were
additionally washed with water and dried over anhydrous Na2SO4.
The solvent was evaporated in vacuo to give 2.98 g of a pale yellow
crude product, which was washed with cold ether to afford 2.78 g
(80%) of 1b as a white solid.
Isoxazole 5b was prepared according to the gram-scale procedure
from 2.20 g (0.007 mol) of 5, 1.09 g (0.004 mol) of I2, and 3.20 g
(0.025 mol) of NOHSO4 in 72% yield (2.22 g).
AUTHOR INFORMATION
Corresponding Author
■
Oksana B. Bondarenko − Department of Chemistry, M. V.
Lomonosov Moscow State University, 119991 Moscow,
Russian Federation; orcid.org/0000-0003-3347-8740;
Email: bondarenko@org.chem.msu.ru
Authors
Georgy L. Karetnikov − Department of Chemistry, M. V.
Lomonosov Moscow State University, 119991 Moscow,
Russian Federation
Arseniy I. Komarov − Department of Chemistry, M. V.
Lomonosov Moscow State University, 119991 Moscow,
Russian Federation
Aleksandr I. Pavlov − Department of Chemistry, M. V.
Lomonosov Moscow State University, 119991 Moscow,
Russian Federation
Svetlana N. Nikolaeva − Department of Chemistry, M. V.
Lomonosov Moscow State University, 119991 Moscow,
Russian Federation
Isoxazole 6b was prepared according to the gram-scale procedure
from 1.55 g (0.006 mol) of 6, 1.80 g (0.009 mol) of Me4NI, and 3.05
g (0.024 mol) of NOHSO4 in 83% yield (1.92 g).
One-Pot Synthesis of 3,5-Diaryl-4-haloisoxazoles 1a−c, 2a−c,
19a, and 19c, from 1,2-Diarylcyclopropanes 16−18 (General
Procedure). Cyclopropane (1 mmol), nitromethane (10 mL), and
NOHSO4 (0.176 g, 1.5 mmol) were loaded into a thoroughly dried
50 mL round-bottom flask equipped with a tightly fitted stopper and a
magnetic stirrer. The reaction mixture was stirred at room
temperature for 1.0−1.5 h; then an additional amount of NOHSO4
(0.117 g, 1 mmol) was added, and stirring was continued until full
consumption of the corresponding 3,5-diaryl-4,5-dihydroisoxazole
(TLC monitoring). Then, the required tetramethylammonium halide
and an additional amount of NOHSO4 were added in agreement with
Table 1. After completion of the reaction, the mixture was neutralized
with a 0.1 M solution of NaHCO3, and the organic compounds were
extracted with chloroform (3 × 20 mL). The organic extracts were
combined, washed in series with 10% Na2SO3 water solution, water,
and dried over sodium sulfate. The solvent was evaporated using a
rotary evaporator. The products were purified by recrystallization
from ethanol to afford the following compounds: 1a, 259 mg (92%
yield); 1b, 329 mg (92% yield); 1c, 252 mg (70% yield); 2a, 90 mg
(70% yield); 2b, 159 mg (74% yield); 2c, 42 mg (92% yield).
4-Bromo-3,5-bis(4-fluorophenyl)isoxazole (19a): 136 mg (93%
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02106
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Foundation for Basic
Research (projects nos. 18-33-01109 and 20-33-90030). The
authors are grateful to Thermo Fisher Scientific, Inc., MS
Analytics (Moscow) and personally to Professor A. A. Makarov
(Thermo Fisher Scientific, Inc.) for providing the mass
spectrometric equipment used in this work. We also acknowl-
edge partial support from the M.V. Lomonosov Moscow State
University Program of Development.
1
yield), white crystalline solid; mp 184−185 °C; H NMR (CDCl3,
400 MHz) δ 8.12 (dd, 2H, JH−H = 8.9, JH−F = 5.3 Hz), 7.88 (dd, 2H,
J
H−H = 8.9, JH−F = 5.3 Hz), 7.22−7.28 (m, 4H); 13C{1H} NMR (101
MHz, CDCl3) δ 164.7, 163.6 (d, 1JC−F = 250.3 Hz), 163.5 (d, 1JC−F
=
253.2 Hz), 160.9, 130.2 (d, 3JC−F = 8.5 Hz), 128.8 (d, 3JC−F = 8.7 Hz),
123.4 (d, 4JC−F = 3.3 Hz), 122.5 (d, 4JC−F = 3.5 Hz), 115.7 (d, 2JC−F
=
REFERENCES
2
■
25.6 Hz), 115.4 (d, JC−F = 26.5 Hz), 88.7. Calcd for C15H8BrF2NO,
%: C, 53.57; H, 2.38; N, 4.17. Found, %: C, 53.68; H, 2.55; N, 4.22.
3,5-Bis(4-fluorophenyl)-4-chloroisoxazole (19c): 94 mg (74%
yield), white crystalline solid; mp 93 °C; 1H NMR (CDCl3, 400
MHz) δ 8.05 (dd, 2H, JH−H = 8.7, JH−F = 5.3 Hz), 7.90 (dd, 2H, JH−H
= 8.7, JH−F = 5.3 Hz), 7.23 (t, 2H, J = 8.7 Hz), 7.22 (t, 2H, J = 8.7
(1) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, Vols. 1 and 2.
(2) Yamada, S.; Knochel, P. Large-scale preparation of aromatic
fluorides via electrophilic fluorination with functionalized aryl-or
heteroarylmagnesium reagents. Synthesis 2010, 14, 2490−2494.
(3) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M.
̈
Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 163.6 (d, JC−3 F = 250.8
1
D.; Stanetty, P. Cross-Coupling Reactions on Azoles with Two and
More Heteroatoms. Eur. J. Org. Chem. 2006, 15, 3283−3307.
(4) Ku, Y.-Y.; Grieme, T.; Sharma, P.; Pu, Y.-M.; Raje, P.; Morton,
H.; King, S. Use of Iodoacetylene as a Dipolarophile in the Synthesis
of 5-Iodoisoxazole Derivatives. Org. Lett. 2001, 3, 4185−4187.
(5) Kumar, J. S. D.; Ho, M. M.; Leung, J. M.; Toyokunia, T.
Convenient Approach to 3,4-Diarylisoxazoles Based on the Suzuki
Cross-Coupling Reaction. Adv. Synth. Catal. 2002, 344, 1146−1151.
1
Hz), 163.5 (d, JC−F = 252.7 Hz), 163.0, 159.5, 129.9 (d, JC−F = 8.5
3
4
Hz), 128.3 (d, JC−F = 8.7 Hz), 123.0 (d, JC−F = 3.3 Hz), 122.3 (d,
4JC−F = 3.3 Hz), 115.8 (d, JC−F = 22.1 Hz), 115.6 (d, JC−F = 21.9
Hz), 103.7; HRMS (ESI) m/z [M + H]+ calcd for C15H9ClF2NO
292.0335, 294.0306; found 292.0338, 294.0308.
2
2
ASSOCIATED CONTENT
■
̈
(6) Kromann, H.; Slok, F. A.; Johansen, T. N.; Krogsgaard-Larsen, P.
sı
* Supporting Information
A convenient synthesis of 4-substituted 3-ethoxy-5-methylisoxazoles
by palladium-catalyzed coupling reactions. Tetrahedron 2001, 57 (11),
2195−2201.
(7) Kalin, J. H.; Zhang, H.; Gaudrel-Grosay, S.; Vistoli, G.;
Kozikowski, A. P. Chiral Mercaptoacetamides Display Enantioselec-
tive Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection
in Cortical Neuron Models of Oxidative Stress. ChemMedChem 2012,
7, 425−439.
(8) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lushington, G. H.;
Larock, R. C. Solution phase synthesis of a diverse library of highly
substituted isoxazoles. J. Comb. Chem. 2008, 10 (5), 658−663.
(9) Li, F.; Hu, Y.; Wang, Y.; Ma, C.; Wang, J. Expeditious Lead
Optimization of Isoxazole-Containing Influenza A Virus M2-S31N
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02106.
1H and 13C NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−1c, 2a−2c, 3a−3c, 4a−4c, 5a−5c, 6a−
6c, 7a−7c, 8a, 8b, 9a, 9b, 10a, 11a, 12a, 12c, 13, 14b,
15b, 15c, 19a, 19c, 20a, 21a, 21b, 22a−22c, 23a−23c,
24, 25, 26, 27b, 27c, 28b, 28c, 29, 30, 31, 32, 33, and
34 (ZIP)
I
https://dx.doi.org/10.1021/acs.joc.0c02106
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The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Inhibitors Using the Suzuki-Miyaura Cross-Coupling Reaction. J. Med.
Chem. 2017, 60, 1580−1590.
(28) Kochetkov, N. K.; Khomutova, E. D. Research in isoxazole
series VIII. Electrophilic substitution in isoxazole. Zh. Obshch. Khim.
1959, 29, 535.
(10) Waldo, J. P.; Larock, R. C. Synthesis of Isoxazoles via
Electrophilic Cyclization. Org. Lett. 2005, 7, 5203−5205.
(11) Kaewsri, W.; Thongsornkleeb, C.; Tummatorn, J.; Ruchirawat,
S. Isomerizable (E/Z)-alkynyl-O-methyl oximes employing TMSCl-
NCS in chlorinative cyclization for the direct synthesis of 4-
chloroisoxazoles. RSC Adv. 2016, 6, 48666−48675.
(29) Morita, T.; Fuse, S.; Nakamura, H. Generation of an 4-
Isoxazolyl Anion Species: Facile Access to Multifunctionalized
Isoxazoles. Angew. Chem., Int. Ed. 2016, 55, 13580−13584.
(30) Belen’kii, L. I.; Chuvylkin, N. D. Relationships and Features of
Electrophilic Substitution Reactions in the Azole Series. Chem.
Heterocycl. Compd. 1997, 32, 1319−1343.
(12) Jackowski, O.; Lecourt, T.; Micouin, L. Direct synthesis of
polysubstituted aluminoisoxazoles and pyrazoles by a metalative
cyclization. Org. Lett. 2011, 13 (20), 5664−5667.
(13) Crossley, J. A.; Browne, D. L. An alkynyliodide cycloaddition
strategy for the construction of iodoisoxazoles. J. Org. Chem. 2010, 75
(15), 5414−5416.
(14) Iglesias, M.; Schuster, O.; Albrecht, M. A new, mild one-pot
synthesis of iodinated heterocycles as suitable precursors for N-
heterocyclic carbene complexes. Tetrahedron Lett. 2010, 51 (41),
5423−5425.
(15) Chhattise, P. K.; Ramaswamy, A. V.; Waghmode, S. B.
Regioselective, photochemical bromination of aromatic compounds
using N-bromosuccinimide. Tetrahedron Lett. 2008, 49 (1), 189−194
and references therein..
(16) Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Reddy, V. S. A mild
and simple regioselective iodination of activated aromatics with iodine
and catalytic ceric ammonium nitrate. Tetrahedron Lett. 2007, 48, 81−
83 and references therein..
(17) Day, R. A.; Blake, J. A.; Stephens, C. E. Convenient and
improved halogenation of 3, 5-diarylisoxazoles using N-halosuccini-
mides. Synthesis 2003, 10, 1586−1590 and references therein..
(18) Bondarenko, O. B.; Vinogradov, A. A.; Danilov, P. A.;
Nikolaeva, S. N.; Gavrilova, A. Yu.; Zyk, N. V. Nitrosation of 2-
aryl-1,1-dibromocyclopropanes: synthesis of 3-aryl-5-bromoisoxa-
zoles. Tetrahedron Lett. 2015, 56, 6577−6579.
(19) Bondarenko, O. B.; Gavrilova, A. Y.; Nikolaeva, S. N.; Zyk, N.
V. Transformations of gem-dibromoarylcyclopropanes under nitro-
sation conditions on treatment with NOCl·(SO3)n. Russ. Chem. Bull.
2016, 65 (5), 1225−1231.
(20) Bondarenko, O. B.; Komarov, A. I.; Karetnikov, G. L. Method
for producing halogenated derivatives of aromatic and heteroaromatic
compounds. RF Patent 2711558. Inventions Utility Models. Official
Bulletin of the Federal Service for Intellectual Property (Rospatent) 2020,
no. 20.
(21) Quilico, A.; Justoni, R. New researches in the ioxazole group II.
Halogen derivatives. Rend. ist. lombardo sci. 1936, 69, 587−601; Chem.
Abstr. 1938, 32, 7455.
(22) Shabarov, Yu. S.; Saginova, L. G.; Gazzaeva, R. A. Synthesis of
isoxazolines from arylcyclopropanes under nitrosation conditions.
Chem. Heterocycl. Compd. 1983, 19, 589.
(23) Mizuno, K.; Ichinose, N.; Tamai, T.; Otsuji, Y. Insertion of
nitrogen oxide and nitrosonium ion into the cyclopropane ring: a new
route to 2-isoxazolines and its mechanistic studies. J. Org. Chem. 1992,
57, 4669−4675.
(24) Lin, S.-T.; Kuo, S.-H.; Yang, F.-M. Reaction of Halogenated
Cyclopropanes and Nitrosyl Cation: Preparation of Isoxazoles. J. Org.
Chem. 1997, 62, 5229−5231.
(25) Bondarenko, O. B.; Garaev, Z. M.; Komarov, A. I.; Kuznetsova,
L. I.; Gutorova, S. V.; Skvortsov, D. A.; Zyk, N. V. Nitrosylsulfuric
acid in the synthesis of 5-chloroisoxazoles from 1,1-dichlorocyclo-
propanes. Mendeleev Commun. 2019, 29, 419−420.
(26) Bondarenko, O. B.; Komarov, A. I.; Kuznetsova, L. I.;
Nikolaeva, S. N.; Gavrilova, A. Y.; Zyk, N. V. Nitrosylsulfuric acid
as an oxidant in the synthesis of 3, 5-diarylisoxazoles. Russ. Chem. Bull.
2018, 67 (3), 517−520.
(27) Bondarenko, O. B.; Komarov, A. I.; Karetnikov, G. L.;
Nikolaeva, S. N.; Zyk, N. V. Nitrosylsulfuric acid as a tandem reagent
in the synthesis of 3, 5-diarylisoxazoles from 1,2-diarylcyclopropanes.
Russ. Chem. Bull. 2019, 68 (6), 1200−1203.
(31) Kochetkov, N. K.; Sokolov, S. D.; Vagurtova, N. M. Research in
isoxazole series XII. Iodination and bromination of isoxazoles. Zh.
Obshch. Khim. 1961, 31, 2326−2333.
(32) Englert, S. M. E.; McElvain, S. M. Bromination of Pyridine. J.
Am. Chem. Soc. 1929, 51, 863−866.
(33) Gompper, R.; Ruhle, H. Untersuchungen in der Azolreihe, IX
̈
Die Halogenierung substituierter Oxazole. Lieb. Ann. Chem. 1959,
626, 83−91.
(34) Radner, F. Lower Nitrogen Oxide Species as Catalysts in a
Convenient Procedure for the Iodination of Aromatic Compounds. J.
Org. Chem. 1988, 53, 3548−3553.
(35) Merkushev, E. V. Advances in the Synthesis of Aromatic Iodo-
compounds. Russ. Chem. Rev. 1984, 53 (4), 343−350 and references
therein..
(36) Stephens, C. E.; Arafa, R. K. 3,5-Diarylisoxazoles: Individu-
alized three-step synthesis and isomer determination using 13C NMR
or mass spectroscopy. J. Chem. Educ. 2006, 83 (9), 1336−1340.
(37) LaLonde, R. T.; Ferrara, P. B. Reactions of Arylcyclopropanes
with N-Bromosuccinimide in Hydroxylic Solvents. J. Org. Chem. 1972,
37, 2502−2505.
(38) Yu, J.; Edjah, B.; Argueta-Gonzalez, H.; Ross, S.; Gaulden, P.;
Shanderson, R.; Dave, J.; Baumstark, A. L. 13C NMR spectroscopy of
heterocycles: 3,5-diaryl-4-bromoisoxazoles. Heterocycl. Commun.
2015, 21 (5), 279−283.
(39) Waldo, J. P.; Larock, R. C. The synthesis of highly substituted
isoxazoles by electrophilic cyclization: an efficient synthesis of
valdecoxib. J. Org. Chem. 2007, 72, 9643−9647.
(40) Kim, K. J.; Kim, K. Reactions of 5-substituted 3-alkyl-and 3-
aryl-isoxazoles with tetrasulfur tetranitride antimony pentachloride
complex (S4N4·SbCl5): complete regioselective formation of 4-
substituted 3-acyl-and 3-aroyl-1,2,5-thiadiazoles and their mechanism
of formation. J. Chem. Soc., Perkin Trans. 1 1998, No. 14, 2175−2180.
(41) Haddad, T.; Gershman, R.; Dilis, R.; Labaree, D.; Hochberg, R.
B.; Hanson, R. N. Synthesis and evaluation of 4-(substituted styryl/
alkenyl)-3,5-bis(4-hydroxyphenyl)-isoxazoles as ligands for the estro-
gen receptor. Bioorg. Med. Chem. Lett. 2012, 22, 5999−6003.
(42) Barluenga, J.; Miguel, T.; Lopez, L. A.; Jardon, J.; Gotor, V. J.
Chem. Res. 1987, 7, 1763−1774.
(43) Stefani, H. A.; Pereira, C. M. P.; Almeida, R. B.; Braga, R. C.;
Guzen, K. P.; Cella, R. A mild and efficient method for halogenation
of 3,5-dimethyl pyrazoles by ultrasound irradiation using N-
halosuccinimides. Tetrahedron Lett. 2005, 46, 6833−6837.
́
́
́
́
́
(44) Gonda, Z.; Kovacs, S.; Weber, C.; Gati, T.; Meszaros, A.;
́
Kotschy, A.; Novak, Z. Efficient copper-catalyzed trifluoromethylation
of aromatic and heteroaromatic iodides: The beneficial anchoring
effect of borates. Org. Lett. 2014, 16, 4268−4271.
(45) Hirose, Y.; Yamazaki, M.; Nogata, M.; Nakamura, A.; Maegawa,
T. Aromatic halogenation using N-halosuccinimide and PhSSiMe3 or
PhSSPh. J. Org. Chem. 2019, 84, 7405−7410.
̌
(46) Bedrac, L.; Iskra, J. Iodine (I) Reagents in Hydrochloric Acid-
Catalyzed Oxidative Iodiation of Aromatic Compounds by Hydrogen
Peroxide and Iodine. Adv. Synth. Catal. 2013, 355, 1243−1248.
(47) Nishii, Y.; Ikeda, M.; Hayashi, Y.; Kawauchi, S.; Miura, M.
Triptycenyl Sulfide: A Practical and Active Catalyst for Electrophilic
Aromatic Halogenation Using N-Halosuccinimides. J. Am. Chem. Soc.
2020, 142, 1621−1629.
(48) Suzuki, Y.; Ishiwata, Y.; Moriyama, K.; Togo, H. Desulfonylox-
yiodination of arenesulfonic acids with mCPBA and molecular iodine.
Tetrahedron Lett. 2010, 51, 5950−5953.
J
https://dx.doi.org/10.1021/acs.joc.0c02106
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
̈
(49) Mockel, R.; Hilt, G. Synthesis of polysubstituted iodobenzene
derivatives from alkynylsilanes and 1, 3-dienes via Diels-alder/
oxidation/iodination reaction sequence. Org. Lett. 2015, 17 (7),
1644−1647.
(50) Haszeldine, R. N.; Sharpe, A. G. The reactions of metallic salts
of acidss with halogens. Part II. The interaction of silver
trifluoroacetate or silver perchlorate and halogens in various solvents.
J. Chem. Soc. 1952, 177, 993−1001.
(51) Dewkar, G. K.; Narina, S. V.; Sudalai, A. NaIO4-mediated
selective oxidative halogenation of alkenes and aromatics using alkali
metal halides. Org. Lett. 2003, 5, 4501−4504.
(52) Santos, I. S.; Guerra, F. S.; Bernardino, L. F.; Fernandes, P. D.;
Hamerski, L.; Silva, B. V. A Facile Synthesis of Novel Isatinspiroox-
azine Derivatives and Potential in vitro Anti-Proliferative Activity. J.
Braz. Chem. Soc. 2018, 30, 198−209.
(53) Tsedere, D. G.; Grinberg, B. A.; Roska, A. S.; Zorin, L. M.;
Zhungietu, G. I.; Prikulis, A. A. Reversible monoamine oxidase
inhibitors in the indolinone series. Pharm. Chem. J. 1984, 18, 304−
307.
(54) Moorthy, J. N.; Senapati, K.; Kumar, S. IBX- I2 Redox Couple
for Facile Generation of IOH and I+: Expedient Pprotocol for
Iodohydroxylation of Olefins and Iodination of Aromatics. J. Org.
Chem. 2009, 74, 6287−6290.
(55) Castanet, A. S.; Colobert, F.; Broutin, P. E. Mild and
regioselective iodination of electron-rich aromatics with N-iodosucci-
nimide and catalytic trifluoroacetic acid. Tetrahedron Lett. 2002, 43
(29), 5047−5048.
(56) Morita, T.; Fuse, S.; Nakamura, H. Generation of an 4-
Isoxazolyl Anion Species: Facile Access to Multifunctionalized
Isoxazoles. Angew. Chem. 2016, 128 (43), 13778−13782.
́
(57) Rodríguez-Franco, M. I.; Dorronsoro, I.; Hernandez-Higueras,
A. I.; Antequera, G. A mild and efficient method for the regioselective
iodination of pyrazoles. Tetrahedron Lett. 2001, 42 (5), 863−865.
K
https://dx.doi.org/10.1021/acs.joc.0c02106
J. Org. Chem. XXXX, XXX, XXX−XXX