Ultrasound-Promoted Radical Synthesis of 5-Methylselanyl-4,5-dihydroisoxazoles

Article abstract of DOI:10.1002/ejoc.201901611

The ultrasound-promoted synthesis of 5-methylselanyl-4,5-dihydroisoxazoles through the radical cyclization of unsaturated oximes with diaryl diselenides using Oxone as an oxidant and ethanol as the solvent is described. The key step of the reaction is the

Full text of DOI:10.1002/ejoc.201901611

DOI: 10.1002/ejoc.201901611
Full Paper
Organoselenium Compounds
Ultrasound-Promoted Radical Synthesis of 5-Methylselanyl-4,5-
dihydroisoxazoles
Daniela R. Araujo,[a] Yanka R. Lima,[a] Angelita M. Barcellos,[a] Márcio S. Silva,[a]
Raquel G. Jacob,[a] Eder J. Lenardão,[a] Luana Bagnoli,[b] Claudio Santi,[b] and
Gelson Perin*[a]
Abstract: The ultrasound-promoted synthesis of 5-methyl- cals. The reactions proceed efficiently using several oximes and
selanyl-4,5-dihydroisoxazoles through the radical cyclization of diselenides containing both electron-withdrawing and electron-
unsaturated oximes with diaryl diselenides using Oxone® as an donating groups in the aromatic ring. The positive effect of the
oxidant and ethanol as the solvent is described. The key step sonication resulted in high selectivity, short reaction times (15
of the reaction is the ultrasound-initiated homolytic cleavage to 40 min) and moderate to excellent yields of the expected
of KHSO5, leading to the formation of sulfate and hydroxyl radi- products (60–93 %).
Introduction
The search for new methods for the synthesis of heterocyclic
compounds has been increasing, once these molecules have a
significant importance in the pharmaceutical field.[1] More spe-
cifically, isoxazoles are outstanding due to their biological activ-
ities, such as antifungal,[2] antiparasitic[3] and anticancer.[4] Be-
sides, this scaffold is used in the synthesis of more complex
molecules.[5] Another important class of compounds are the or-
ganoselenium ones, which are used both as intermediate in
organic synthesis and in drug discovery.[6] There are several
methods to introduce selenium into organic molecules, which
include the use of nucleophilic,[7] electrophilic[8] and radical
Se-centered reagents.[9]
Among the methodologies described to prepare isoxazole
derivatives, the 1,3-dipolar cycloaddition of alkenes and oximes
(Scheme 1a)[10] or oxime chlorides (Scheme 1b) are the most
atom-efficient.[11] However, the preparation of selenium-con-
Scheme 1. Previous strategies vs. present work.
taining isoxazole derivatives has been scarcely described. For
example, Se-containing 4,5-dihydroisoxazoles or isoxazolines
were obtained through the selenofunctionalization of ꢀ,γ-un-
thesis, the so-called sonochemistry, has emerged in key steps
saturated oximes (Scheme 1c; only two examples)[12] and by
of the synthesis of several compounds, including 3-(5,6-di-
the reaction between hydroximoyl chlorides and allyl-phenyl-
hydropyrazinyliden)-1H-indol-2-ones[15] dihydropyranone, di-
selenide (Scheme 1d).[13]
hydropyrano[2,3-d][1,3]dioxinedione derivatives,[16] and linked
A way to make organic synthesis more environmentally be-
bis-heterocycle peptidomimetics.[17] Sonochemistry can acceler-
nign is by using efficient energy sources, such as ultrasonic irra-
ate and modify the course of reactions and even generate inter-
diation.[14] In recent years, the use of ultrasound in organic syn-
mediates that would not be feasible in conventional synthe-
sis.[18] Recently, our research group has described the efficient
[a] Laboratório de Síntese Orgânica Limpa – LASOL, Federal University of
synthesis of 3-selanylindoles[19] and selenium-containing chry-
Pelotas – UFPel,
P.O. Box 354, 96010-900, Pelotas – RS, Brazil
sin derivatives[20] using ultrasonic irradiation.
E-mail: gelson_perin@ufpel.edu.br
http://lattes.cnpq.br/5962449538872950
In parallel, Oxone® is an environmentally friendly oxidant
used in the transformation of a wide range of organic com-
[b] Department of Pharmaceutical Sciences, University of Perugia,
pounds. This oxidant is commercially available as a blend of
Via del Liceo, 1, Perugia (PG), Italy
three inorganic salts (2KHSO5·KHSO4·K2SO4), being potassium
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901611.
peroxymonosulfate (KHSO5) the active species.[21] Interestingly,
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Oxone® decomposition leads to the formation of free radicals the reaction. By using a lower amount of Oxone® (0.125 mmol),
by homolytic cleavage of KHSO5. This decomposition can be there was no total consumption of the starting materials after
accelerated by homogeneous catalysis in the presence of transi- 40 min of sonication, and the desired product 3a was obtained
tion metals (e.g., Co2+, Mn2+, Fe2+), or by ultraviolet light irradia-
tion.[22] The use of Oxone® combined with ultrasound irradia-
tion (US) was explored in environmental chemistry, in the deg-
radation of the cationic dye cresol red.[23] It was observed an
acceleration in the degradation rate due to the formation in
situ of hydroxyl radical and sulfate radical anion (HO· + SO4·–),
which are powerful oxidant species. In the recent years, Oxone®
has been used as a mild and green oxidant in the synthesis of
valuable selenium-containing molecules.[24]
in only 42 % yield (Table 1, entry 2). When an excess of Oxone®
was used (0.300 mmol), the starting materials were consumed
in 20 min and the product was isolated in 85 % yield (Table 1,
entry 3). No product was observed in the absence of Oxone®,
evidencing that this reagent is crucial to trigger the radical cy-
clization step in the reaction (Table 1, entry 4 and see a plausi-
ble mechanism below). The use of an excess of diphenyl disele-
nide 2a (0.250 mmol) was not effective in increasing the reac-
tion yield, giving the product 3a in 80 % yield (Table 1, entry
Considering the synergistic effect of Oxone® under sonica- 5). Subsequently, the reaction was tested in methanol, polyeth-
tion, and the importance of organoselenium compounds and
isoxazoline derivatives, we have designed an ultrasound-based
protocol to prepare Se-containing isoxazolines. This new strat-
egy involves the Oxone®/ultrasound-promoted intermolecular
radical cyclization of ꢀ,γ-unsaturated oximes with diorganyl dis-
elenides, affording the respective 5-methylselanyl-4,5-dihydro-
isoxazoles (Scheme 1e).
ylene glycol-400 (PEG-400), glycerol, water, acetonitrile and di-
methylformamide (Table 1, entries 6–11). When MeOH, MeCN
and DMF were used, good yields were obtained; however, con-
sidering that EtOH is a more environmentally benign solvent
because it can be obtained from biomass, it was chosen in this
synthesis. Based on the results depicted in Table 1, and taking
into consideration the toxicity of the tested solvents, the best
reaction condition was defined as the sonication of a mixture
of 0.250 mmol of oxime 1a, 0.125 mmol of diphenyl diselenide
2a and 0.250 mmol of Oxone® in ethanol as the solvent (2.0 mL)
(Table 1, entry 1).
Results and Discussion
Combining the environmental and economic advantages of us-
ing Oxone® under ultrasonic irradiation, a feasibility study was
carried out to obtain 5-methylselanyl-4,5-dihydroisoxazoles 3.
Initially, a test was performed using 0.250 mmol of oxime 1a,
0.125 mmol of diselenide 2a, 0.250 mmol of Oxone® and eth-
anol (2.0 mL) as solvent under ultrasonic irradiation at an ampli-
tude of 60 % and a frequency of 20 kHz (Table 1, entry 1). After
20 min of sonication, the total consumption of the starting ma-
terials was observed (monitored by TLC), and the expected 5-
methylselanyl-4,5-dihydroisoxazole 3a was obtained in 85 %
yield. Other conditions to prepare 3a were investigated, includ-
ing the use of different amounts of the starting material 2a and
In order to evaluate the role of the ultrasound irradiation in
the synthesis of 5-methylselanyl-4,5-dihydroisoxazoles, addi-
tional studies were carried out using other energy sources, like
thermal heating (oil bath), focused microwaves (MW) and the
use of an ultrasonic cleaner bath (Table 2). As mentioned be-
fore, the product was obtained in 85 % yield in only 20 min
using the ultrasound probe type equipment (Table 2, entry 1).
When a cleaner ultrasound bath was used however, a longer
reaction time was necessary to obtain a similar yield of 3a (2 h,
82 %) (Table 2, entry 2). When a conventional heating system
(oil bath) was used at 65 ºC, product 3a was obtained in 72 %
of Oxone®, as well as, the nature of the solvent (Table 1, entries yield after stirring for 18 h (Table 2, entry 3). Finally, the same
2–11). Firstly, we studied the effect of the Oxone® amount in reaction was performed using MW irradiation at two different
Table 1. Optimization of the reaction conditions.[a]
Entry
2a [mmol]
Oxone® [mmol]
Solvent
Time [min]
Yield [%][b]
1
2
3
4
5
6
7
8
0.125
0.125
0.125
0.125
0.250
0.125
0.125
0.125
0.125
0.125
0.125
0.250
0.125
0.30
EtOH
EtOH
EtOH
EtOH
20
40
20
60
20
20
20
15
10
30
30
85
42
85
NR
80
86
60
20
20
90
85
–
0.250
0.250
0.250
0.250
0.250
0.250
0.250
EtOH
MeOH
PEG-400
Glycerol
H2O
MeCN
DMF
9
10
11
[a] A mixture of 1a (0.250 mmol), 2a, Oxone® and the solvent (2.0 mL) in a glass tube was sonicated (60 % of amplitude) for the time indicated in the Table.
[b] Isolated yields after column chromatography. NR: no reaction.
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temperatures: 65 °C and 80 °C, and the expected product 3a 85 % yields after 20 min and 30 min, respectively (Scheme 2).
was obtained in 80 % yield after 2.5 h and 2 h, respectively In contrast, electron-rich p-tolyl diselenide 2d (R1 = 4-CH3C6H4)
and p-anisyl diselenide 2e (R1 = 4-CH3OC6H4) afforded the re-
spective products 3d and 3e in 72 % and 60 % yields
(Scheme 2). The moderate yields of products 3d and 3e can
be also attributed to their low stability under the purification
conditions compared to the other derivatives, once it was ob-
served decomposition in this step. The optimal conditions were
successfully applied in the reaction of 2-naphthyl diselenide 2f
with 1a, and the expected product 3f was obtained in 82 %
yield after 20 min of sonication (Scheme 2). The alkyl-substi-
tuted dibutyl diselenide 2g was a good substrate for the reac-
tion, and the desired product 3g was obtained in 85 % yield
after 40 min (R1 = C4H9, Scheme 2).
Also, we examined the reaction between oxime 1a and di-
phenyl telluride and diphenyl disulfide. Unfortunately, in both
cases the desired products were not obtained, even after 2 h
of sonication, and the formation of products of oxidation of the
dichalcogenides was observed. The possibility of performing
these reactions with another oximes 1b–e was also investi-
gated. Oximes containing EDG and EWG at the aromatic ring
efficiently reacted with diphenyl diselenide 2a, affording the
respective products 3h, 3i and 3j in 70 %, 80 % and 72 % yields
after 30–35 min of reaction (Scheme 2). Differently to the ob-
served for the diaryl diselenide counterpart 2, it was not
possible to infer any electronic effect due to the substituents in
the aromatic ring of oximes 1b–d. 2-Naphthyl oxime 1e was
also a suitable substrate for the reaction with 2a, and the ex-
(Table 2, entries 4 and 5). These results clearly indicate the ad-
vantage of using the ultrasound probe to promote this reaction.
Table 2. Different energy sources in the synthesis of 3-phenyl-5-[(phenyl-
selanyl)methyl]-4,5-dihydroisoxazole 3a.[a]
Entry
Energy source
Time
Yield of 3a [%][b]
1
2
3
4
5
ultrasound probe
ultrasound cleaner bath
oil bath[c]
20 min
2 h
18 h
2.5 h
2 h
85
82
72
80
80
microwave[c]
microwave[d]
[a] The reaction was carried out using 1a (0.250 mmol), 2a (0.125 mmol),
Oxone® (0.250 mmol) in EtOH (2.0 mL) in a glass vial. [b] Isolated yields after
column chromatography. [c] The reaction was carried out at 65 °C. [d] The
reaction was carried out at 80 °C.
Once the best conditions were determined, the methodol-
ogy was extended to different substrates, in order to evaluate
its generality and robustness in the synthesis of different
organoselanyl-4,5-dihydroisoxazoles 3 (Scheme 2). Firstly, the
effect of electron-withdrawing groups (EWG) and electron-do-
nor ones (EDG) attached to the aromatic ring of the diselenide
2 was evaluated in the reaction with 1-phenylbut-3-en-1-one
oxime 1a (Scheme 2). In general, electron-deficient diaryl di-
selenides were more reactive substrates than the electron-rich
ones, affording higher yields of the respective products. For in-
stance, para-substituted diaryl diselenides 2b (R1 = 4-ClC6H4)
and 2c (R1 = 4-FC6H4) reacted with 1a to afford the respective
Se-containing 4,5-dihydroisoxazoles 3b and 3c in 93 % and
Scheme 2. Synthesis of 5-methylselanyl-4,5-dihydroisoxazoles 3a–k.
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Scheme 3. Control experiments and mechanistic studies.
pected product 3k was obtained in 75 % yield after 40 min did not give the expected product 3a, and only the intermedi-
(Scheme 2).
ate 5 and the starting materials were observed by GC/MS analy-
sis (Scheme 3d).
Aiming to gain a better understanding of this ultrasound-
promoted process, some control experiments and mechanistic
studies were conducted in the reaction of 1a with 2a
(Scheme 3). As observed before, Oxone® is essential to the for-
mation of the desired compound 3a under ultrasound. Thus, to
verify the involvement of radical intermediates in the reaction,
the radical scavenger hydroquinone (3.0 equiv.) was added to
the standard reaction. After 20 min of sonication, no product
3a was observed, indicating that a radical pathway is involved.
In order to verify the influence of the energy source, the same
reaction was performed using microwave irradiation at 65 °C,
and after 2 h, product 3a was isolated in 78 % yield
(Scheme 3a). This observation indicates that by switching from
Following, the addition sequence was reversed, i.e., firstly di-
selenide 2a and Oxone® reacted for 20 min under ultrasound;
then, oxime 1a and more Oxone® were added in the reaction
vial. The resulting mixture was sonicated for additional 45 min,
however only the starting materials were present at the end of
the process (Scheme 3e). Taken together, the outcomes of the
control experiments clearly indicate that the energy source in-
fluences the reaction mechanism, with the ultrasound irradia-
tion promoting the formation of the product 3a via a radical
pathway, while under microwave or conventional heating the
reaction occurs mainly by an ionic pathway.
Based on the literature[12,24] and in our own results, two plau-
ultrasound to microwave, the reaction pathway changes from sible mechanisms for the formation of 5-methylselanyl-4,5-di-
predominantly radical to ionic. When 2,2,6,6-tetramethylpiper- hydroisoxazoles 3 were proposed, as illustrated in Scheme 4. In
idin-1-oxyl (TEMPO, 3.0 equiv.) was used as a radical scavenger the radical pathway, the first step is the formation of HO·and
·–
under the standard conditions, the adduct 4 was obtained in SO4 from the ultrasound-promoted dissociation of Oxone®.
56 % yield under sonication. This outcome is like the observed Following, the hydroxyl radical reacts with oxime 1a to form
by Yu and Cai,[12] and it corroborates the involvement of a radi- water and the oxygen-centered radical intermediate I, which
cal pathway under ultrasound. On the other hand, under micro- undergoes a radical cyclization leading to the 5-methyl-4,5-di-
wave and conventional heating (oil bath, 65 °C) the concomi- hydroisoxazole radical II. Then, intermediate II reacts with di-
tant formation of products 3a and 4 occurred (determined by phenyl diselenide 2a to form the desired product 3a and a
GC/MS), indicating that ionic and radical mechanisms co-exist radical PhSe·(Scheme 4a). When the ionic mechanism is operat-
(Scheme 3b). In order to verify if diphenyl diselenide 2a partici- ing, the first step is the formation of the electrophilic species
pates in the initial stage of the reaction, a mixture of oxime 1a, of selenium III and IV, from the reaction of diselenide 2a with
TEMPO and Oxone® was sonicated for 1.5 h, and the adduct 4 Oxone®. The species IV reacts in the acidic reaction medium to
was formed in 56 % yield (Scheme 3c), showing that diphenyl form the more active electrophile IV′. Then, oxime 1a reacts
diselenide 2a does not participate in the first step of the mech- with III and/or IV′ to form the seleniranium intermediate V,
anism. A two step, one-pot reaction starting from the reaction which undergoes an intramolecular attack from the oxygen, fol-
of oxime 1a with Oxone®, to form the isoxazoline intermediate lowed by deprotonation and formation of the desired product
5, followed by the addition of diselenide 2a and more Oxone®, 3a (Scheme 4b).
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Scheme 4. Proposed mechanism.
sition calculations for comparison were executed using the specific
tool included in the Qual Browser module of Xcalibur (Thermo
Fisher Scientific, release 2.0.7) software. The IR spectra were ob-
tained with a Shimadzu – IRAffinity-1. The ultrasound-promoted re-
Conclusions
In this work we have shown for the first time the ultrasound-
promoted synthesis of selenium-containing 4,5-dihydroisox-
azoles starting from ꢀ,γ-unsaturated oximes and diselenides in actions were performed using a Cole Parmer-ultrasonic processor
Model CPX 130, with a maxim power of 130 W, operating at ampli-
tude of 60 % and a frequency of 20 kHz. The temperature of the
reactions under ultrasound was monitored using an Incoterm digi-
tal infrared thermometer model Infraterm (Brazil). Melting point
(m.p.) values were measured in a Marte PFD III instrument with a
0.1 °C precision. Oxone® was purchased from Sigma Aldrich.
the presence of Oxone® and ethanol as the solvent. The key
role of the ultrasound was demonstrated in the mechanistic
studies, directing the reaction via a radical pathway, while the
use of microwaves or conventional heating favors an ionic
mechanism. The method enabled the use of various diorganoyl
diselenides, as well as, different oximes as starting materials,
allowing a diversity of products in yields ranging from good to
excellent and in only 15–40 min of sonication.
General Procedure for the Synthesis of 5-Methylselanyl-4,5-di-
hydroisoxazoles 3: To a 10 mL round-bottomed glass vial, the ap-
propriate oxime 1a–f (0.250 mmol), diselenide 1a–g (0.125 mmol),
Oxone® (0.077 g; 0.250 mmol) and ethanol (2.0 mL) were added.
The ultrasound probe was placed in the reaction vial, and the mix-
ture was sonicated (20 kHz, 60 % of sonic amplitude) for the time
indicated in Scheme 2. The reaction progress was monitored by TLC
in order to evaluate the starting materials consumption. After that,
the product was extracted with ethyl acetate (3× 15.0 mL), the or-
ganic phase was separated, dried with MgSO4 and the solvent
evaporated under reduced pressure. The product was purified by
washing the crude with hexane (2.0 mL) followed by removal of
solvent with a pipette. This addition and removal process was car-
ried out until the solvent used in the extraction became colorless
(around 5 times). The pure product was dried under reduced pres-
sure. All the compounds were properly characterized by MS, FTIR,
1H, 13C and 77Se NMR and HRMS (for the new ones).
Experimental Section
General Remarks: The reactions were monitored by TLC carried
out on Merck silica gel (60 F254) by using UV light as visualizing
agent and 5 % vanillin in 10 % H2SO4 and heat as developing
agents. Baker silica gel (particle size of 0.040–0.063 mm) was used
for flash column chromatography. Hydrogen nuclear magnetic reso-
nance (1H NMR) spectra were obtained at 400 MHz. Spectra were
recorded in CDCl3 solutions. Chemical shifts are reported in ppm,
referenced to tetramethylsilane (TMS) as the external reference.
Coupling constants (J) are reported in Hertz. Abbreviations to de-
note the multiplicity of a particular signal are s (singlet), d (doublet),
dd (doublet of doublet), sex (sextet), t (triplet) and m (multiplet).
Carbon-13 nuclear magnetic resonance (13C NMR) spectra were ob-
tained at 100 MHz. Chemical shifts are reported in ppm, referenced
3-Phenyl-5-[(phenylselanyl)methyl]-4,5-dihydroisoxazole
to the solvent peak of CDCl3. Selenium-77 nuclear magnetic reso- (3a):[17] Yield: 0.067 g (85 %). White solid; m.p. 55–56 °C. Lit.:[17] 54–
nance (77Se NMR) spectra were obtained at 76 MHz, using (PhSe)2
as an internal standard. Low-resolution mass spectra (MS) were ob-
tained with a Shimadzu GC-MS-QP2010 mass spectrometer. High-
resolution mass spectra (HRMS) were obtained for all compounds
56 °C. 1H NMR (CDCl3, 400 MHz) δ [ppm] = 7.56–7.54 (m, 2H); 7.50–
7.47 (m, 2H); 7.35–7.29 (m, 3H); 7.21–7.18 (m, 3H); 4.87–4.79 (m, 1H);
3.36 (dd, J = 16.8, 10.2 Hz, 1H); 3.23 (dd, J = 12.7, 4.6 Hz, 1H); 3.12
(dd, J = 16.8, 6.9 Hz, 1H); 2.92 (dd, J = 12.7, 9.0 Hz, 1H). 13C NMR
on a LTQ Orbitrap Discovery mass spectrometer (Thermo Fisher Sci- (100 MHz, CDCl3) δ [ppm] = 156.1, 133.2, 130.1, 129.4, 129.3, 128.7,
entific). This hybrid system meets the LTQ XL linear ion trap mass
spectrometer and an Orbitrap mass analyzer. The experiments were
performed via direct infusion of sample (flow: 10 μL/min) in the
positive-ion mode using electrospray ionization. Elemental compo-
127.5, 126.8, 126.7, 80.3, 40.0, 31.4. 77Se NMR (76 MHz, CDCl3)
δ [ppm] = 261.28. IR (KBr) ν [cm–1] = 1683.86 (C-O), 1595.13 (C=N).
˜
MS (rel. int., %) m/z: 317 (16.2), 171 (50.7), 146 (100.0), 118 (47.4),
103 (10.2), 77 (92.3).
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5-{[(4-Chlorophenyl)selanyl]methyl}-3-phenyl-4,5-dihydroisox-
azole (3b): Yield: 0.082 g (93 %). Yellowish solid; m.p. 61–63 °C. H
5-[(Butylselanyl)methyl]-3-phenyl-4,5-dihydroisoxazole (3g):
1
Yield: 0.063 g (85 %). Yellowish oil. 1H NMR (CDCl3, 400 MHz) δ
NMR (CDCl3, 400 MHz) δ [ppm] = 7.58–7.54 (m, 2H); 7.43–7.40 (m, [ppm] = 7.68–7.66 (m, 2H); 7.41–7.38 (m, 3H); 4.99–4.91 (m, 1H);
2H); 7.34–7.31 (m, 3H); 7.20–7.16 (m, 2H); 4.86–4.78 (m, 1H); 3.37
(dd, J = 16.7, 10.3 Hz, 1H); 3.20 (dd, J = 12.7, 4.8 Hz, 1H); 3.11 (dd,
J = 16.7, 6.8 Hz, 1H); 2.93 (dd, J = 12.7, 8.5 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ [ppm] = 156.2, 134.6, 133.8, 130.2, 129.4, 129.3,
3.47 (dd, J = 16.7, 10.2 Hz, 1H); 3.21 (dd, J = 16.7, 7.2 Hz, 1H); 2.91
(dd, J = 12.6, 4.7 Hz, 1H); 2.74 (dd, J = 12.6, 8.3 Hz, 1H); 2.68 (t, J =
7.5 Hz, 2H); 1.66 (quint, J = 7.5 Hz, 2H); 1.40 (sext, J = 7.5 Hz, 2H);
0.92 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ [ppm] = 156.1,
128.7, 126.9, 126.7, 80.1, 40.1, 31.8. 77Se NMR (76 MHz, CDCl3) 130.0, 129.5, 128.6, 126.6, 81.0, 40.2, 32.6, 27.4, 24.5, 22.8, 13.5. 77Se
δ [ppm] = 260.95. IR (KBr) ν [cm–1] = 1643.24 (C-O), 1568.13 (C=N).
NMR (76 MHz, CDCl3) δ [ppm] = 128.97. IR (KBr) ν [cm–1] = 1616.35
˜
˜
MS (rel. int., %) m/z: 350 (11.1), 205 (25.0), 190 (8.7), 146 (100.0), 160
(2.4), 111 (1.7), 77 (57.3). HRMS (APCI-QTOF) calculated mass for
C16H14ClNOSe [M]+: 350.9929, found 350.9922.
(C-O), 1568.13 (C=N). MS (rel. int., %) m/z: 297 (3.9), 152 (30.1), 146
(100.0), 118 (25.1), 91 (13.8), 77 (34.3). HRMS (APCI-QTOF) calculated
mass for C14H19NOSe [M]+: 297.0632, found 297.0626.
5-{[(4-Fluorophenyl)selanyl]methyl}-3-phenyl-4,5-dihydroisox-
azole (3c): Yield: 0.071 g (85 %). Yellowish solid; m.p. 70–72 °C. H
1
3-(4-Chlorophenyl)-5-[(phenylselanyl)methyl]-4,5-dihydroisox-
azole (3h):[17] Yield: 0.061 g (70 %). Yellowish solid; m.p. 72–73 °C.
Lit.:[17] 70–71 °C. 1H NMR (CDCl3, 400 MHz) δ [ppm] = 7.50–7.47 (m,
4H); 7.31–7.28 (m, 2H); 7.23–7.20 (m, 3H); 4.88–4.80 (m, 1H); 3.33
(dd, J = 16.8, 10.3 Hz, 1H); 3.23 (dd, J = 12.6, 4.5 Hz, 1H); 3.09 (dd,
J = 16.8, 6.9 Hz, 1H); 2.92 (dd, J = 12.6, 9.0 Hz, 1H). 13C NMR (CDCl3,
100 MHz) δ [ppm] = 155.3, 136.1, 133.3, 129.3, 129.0, 128.6, 127.9,
127.8, 127.6, 80.7, 39.9, 31.3. 77Se NMR (76 MHz, CDCl3) δ [ppm] =
NMR (CDCl3, 400 MHz) δ [ppm] = 7.64–7.62 (m, 2H); 7.57–7.53 (m,
2H); 7.41–7.38 (m, 3H); 7.01–6.95 (m, 2H); 4.91–4.83 (m, 1H); 3.43
(dd, J = 16.8, 10.3 Hz, 1H); 3.23 (dd, J = 12.6, 4.7 Hz, 1H); 3.17 (dd,
J = 16.8, 6.9 Hz, 1H); 2.97 (dd, J = 12.6, 8.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ [ppm] = 162.2 (d, J = 246.4 Hz), 156.1, 135.9 (d,
J = 8.0 Hz), 130.1, 129.3, 128.7, 126.6, 123.1 (d, J = 3.3 Hz), 116.4 (d,
J = 21.4 Hz), 80.2, 40.0, 32.3. 77Se NMR (76 MHz, CDCl3) δ [ppm] =
262.53. IR (KBr) ν [cm–1] = 1683.86 (C-O), 1595.13 (C=N). MS (rel.
259.23. IR (KBr) ν [cm–1] = 1637.56 (C-O), 1583.56 (C=N). MS (rel.
˜
˜
int., %) m/z: 350 (22.0), 281 (24.7), 207 (63.6), 157 (21.0), 91 (100.0),
int., %) m/z: 335 (4.9), 206 (19.5), 189 (15.6), 146 (54.6), 77 (41.2), 40
(100.0). HRMS (APCI-QTOF) calculated mass for C16H14FNOSe [M]+:
335.0225, found 335.0219.
77 (51.1), 41 (57.7).
3-(4-Fluorophenyl)-5-[(phenylselanyl)methyl]-4,5-dihydroisox-
azole (3i):[17] Yield: 0.067 g (80 %). White solid; m.p. 81–82 °C.
Lit.:[17] 83–84 °C. 1H NMR (CDCl3, 400 MHz) δ [ppm] = 7.63–7.60 (m,
2H); 7.57–7.54 (m, 2H); 7.30–7.26 (m, 3H); 7.08 (t, J = 8.7 Hz, 2H);
4.94–4.87 (m, 1H); 3.41 (dd, J = 16.8, 10.3 Hz, 1H); 3.30 (dd, J = 12.6,
4.5 Hz, 1H); 3.17 (dd, J = 16.8, 6.9 Hz, 1H), 2.99 (dd, J = 12.6, 9.0 Hz,
1H). 13C NMR (CDCl3, 100 MHz) δ [ppm] = 163.7 (d, J = 249.2 Hz),
155.2, 133.2, 129.3, 128.6 (d, J = 8.4 Hz), 127.6, 125.7 (d, J = 3.4 Hz),
115.8 (d, J = 21.8 Hz), 80.5, 40.1, 31.3. 77Se NMR (76 MHz, CDCl3) δ
3-Phenyl-5-[(p-tolylselanyl)methyl]-4,5-dihydroisoxazole (3d):
Yield: 0.060 g (72 %). Orange oil. 1H NMR (CDCl3, 400 MHz) δ
[ppm] = 7.64–7.62 (m, 2H); 7.47–7.44 (m, 2H); 7.40–7.38 (m, 3H);
7.10–7.08 (m, 2H); 4.91–4.83 (m, 1H); 3.42 (dd, J = 16.8, 10.3 Hz, 1H);
3.26 (dd, J = 12.5, 4.5 Hz, 1H); 3.19 (dd, J = 16.8, 6.8 Hz, 1H); 2.93
(dd, J = 12.5, 9.2 Hz, 1H); 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
[ppm] = 156.1, 140.4, 133.2, 129.4, 129.3, 128.7, 127.5, 126.6, 126.5,
80.2, 40.2, 31.4, 21.4. 77Se NMR (76 MHz, CDCl3) δ [ppm] = 255.02.
IR (KBr) ν [cm–1] = 1610.38 (C-O), 1572.82 (C=N). MS (rel. int., %)
˜
[ppm] = 262.32. IR (KBr) ν [cm–1] = 1643.24 (C-O), 1516.49 (C=N).
˜
m/z: 331 (12.0), 207 (12.4), 171 (12.6), 146 (68.6), 91 (100.0), 77 (51.0).
HRMS (APCI-QTOF) calculated mass for C17H17NOSe [M]+: 331.0475,
found 331.0470.
MS (rel. int., %) m/z: 335 (17.4), 172 (64.7), 164 (100.0), 136 (39.1),
109 (26.7), 95 (44.3), 77 (32.1).
5-{[(4-Methoxyphenyl)selanyl]methyl}-3-phenyl-4,5-dihydro-
isoxazole (3e): Yield: 0.052 g (60 %). Yellowish solid; m.p. 61–63 °C.
1H NMR (CDCl3, 400 MHz) δ [ppm] = 7.57–7.55 (m, 2H); 7.44 (d, J =
8.8 Hz, 2H); 7.34–7.30 (m, 3H); 6.75 (d, J = 8.8 Hz, 2H); 4.82–4.74 (m,
1H); 3.72 (s, 3H); 3.35 (dd, J = 16.8, 10.3 Hz, 1H); 3.15–3.08 (m, 2H);
2.82 (dd, J = 12.5, 9.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ [ppm] =
159.7, 156.1, 138.2, 136.1, 130.1, 128.7, 126.7, 118.4, 115.0, 80.5, 55.3,
3-(4-Tolyl)-5-[(phenylselanyl)methyl]-4,5-dihydroisoxazole
(3j):[17] Yield: 0.060 g (72 %). White solid; m.p. 60–61 °C. Lit.:[17] 59–
60 °C. 1H NMR (CDCl3, 400 MHz) δ [ppm] = 7.57–7.51 (m, 4H); 7.29–
7.26 (m, 3H); 7.21–7.18 (m, 2H); 4.92–4.84 (m, 1H); 3.42 (dd, J = 16.8,
10.2 Hz, 1H); 3.30 (dd, J = 12.6, 4.5 Hz, 1H); 3.18 (dd, J = 16.8, 6.8 Hz,
1H); 2.98 (dd, J = 12.6, 9.0 Hz, 1H); 2.38 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ [ppm] = 156.1, 137.7, 133.7, 130.1, 129.4, 128.6, 126.6,
124.7, 80.4, 40.0, 31.6, 21.1. 77Se NMR (76 MHz, CDCl3) δ [ppm] =
40.0, 32.3. 77Se NMR (76 MHz, CDCl3) δ [ppm] = 252.33. IR (KBr) ν
˜
[cm–1] = 1615.07 (C-O), 1591.61 (C=N). MS (rel. int., %) m/z: 347
(48.6), 187 (46.8), 146 (98.8), 121 (100.0), 77 (90.5), 41 (41.6). HRMS
(APCI-QTOF) calculated mass for C17H17NO2Se [M]+: 347.0425, found
347.0419.
262.29. IR (KBr) ν [cm–1] = 1637.56 (C-O), 1597.96 (C=N). MS (rel.
˜
int., %) m/z: 331 (19.9), 174 (12.2), 160 (100.0), 132 (39.9), 105 (19.1),
91 (80.6), 65 (26.8).
5-[(Naphthalen-2-ylselanyl)methyl]-3-phenyl-4,5-dihydroisox- 3-(Naphthalen-2-yl)-5-[(phenylselanyl)methyl]-4,5-dihydroisox-
1
azole (3f): Yield: 0.075 g (82 %). Yellowish oil. 1H NMR (CDCl3,
400 MHz) δ [ppm] = 8.34 (d, J = 8.8, 1H); 7.82–7.35 (m, 3H); 7.54–
7.43 (m, 4H); 7.33–7.29 (m, 4H); 4.79–4.71 (m, 1H); 3.33 (dd, J = 16.8,
10.3 Hz, 1H); 3.25 (dd, J = 12.4, 4.6 Hz, 1H); 3.11 (dd, J = 16.8, 10.3,
azole (3k): Yield: 0.069 g (75 %). Yellowish solid; m.p. 72–73 °C. H
NMR (CDCl3, 400 MHz) δ [ppm] = 7.94–7.91 (m, 1H); 7.82–7.79 (m,
4H); 7.57–7.54 (m, 2H); 7.50–7.48 (m, 2H); 7.27–7.26 (m, 3H); 4.97–
4.89 (m, 1H); 3.50 (dd, J = 16.7, 10.2 Hz, 1H); 3.34–3.25 (m, 2H); 3.0
1H); 2.95 (dd, J = 12.4, 8.9, 1H). 13C NMR (100 MHz, CDCl3) δ [ppm] = (dd, J = 12.6, 9.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ [ppm] =
156.1, 134.4, 134.1, 133.5, 130.1, 129.4, 129.1, 128.8, 128.7, 127.8, 156.3, 133.9, 133.1, 132.9, 129.2, 128.7, 128.4, 128.3, 127.7, 127.5,
127.6, 127.0, 126.7, 126.4, 125.8, 80.4, 40.1, 31.6. 77Se NMR (76 MHz,
127.1, 126.9, 126.6, 123.4, 80.5, 39.9, 31.3. 77Se NMR (76 MHz, CDCl3)
CDCl ) δ [ppm] = 262.37. IR (KBr) ν [cm–1] = 1643.93 (C-O), 1591.27 δ [ppm] = 262.70. IR (KBr) ν [cm–1] = 1657.32 (C-O), 1582.21 (C=N).
˜
˜
3
(C=N). MS (rel. int., %) m/z: 367 (20.6), 222 (26.1), 206 (34.4), 146
(43.0), 141 (56.3), 77 (51.6). HRMS (APCI-QTOF) calculated mass for
C20H17NOSe [M]+: 367.0475, found 367.0470.
MS (rel. int., %) m/z: 367 (20.0), 196 (100.0), 172 (41.5), 127 (68.3),
115 (12.7), 95 (44.3), 77 (30.), 41 (47.8). HRMS (APCI-QTOF) calculated
mass for C20H17NOSe [M]+: 367.0475, found 367.0470.
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Received: November 3, 2019
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Full Paper
Organoselenium Compounds
D. R. Araujo, Y. R. Lima, A. M. Barcellos,
M. S. Silva, R. G. Jacob, E. J. Lenardão,
L. Bagnoli, C. Santi, G. Perin* ......... 1–8
An ultrasound-promoted method to aryl diselenides using Oxone® as an
synthesize 5-methylselanyl-4,5-dihy- oxidant and ethanol as the solvent is
droisoxazoles through the radical cycli- described.
Ultrasound-Promoted Radical Syn-
thesis of 5-Methylselanyl-4,5-dihy-
droisoxazoles
zation of unsaturated oximes with di-
DOI: 10.1002/ejoc.201901611
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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim