Dehydration of isoxazoline N-oxides under electrophilic conditions – an alternative approach toward 3-haloisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2021.153106

A new method was developed for the synthesis of fully substituted 3-haloisoxazoles. This process includes the synthesis of isoxazoline N-oxides from α-halonitroalkenes and subsequent dehydration mediated by the silyl triflate/triethylamine system.

Full text of DOI:10.1016/j.tetlet.2021.153106

Tetrahedron Letters 73 (2021) 153106
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dehydration of isoxazoline N-oxides under electrophilic conditions – An
alternative approach toward 3-haloisoxazoles
Anastasia A. Fadeeva a,b, Sema L. Ioffe a, Andrey A. Tabolin a,
⇑
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, Moscow 119991, Russia
b Higher Chemical College, D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method was developed for the synthesis of fully substituted 3-haloisoxazoles. This process
Received 26 March 2021
Revised 13 April 2021
Accepted 16 April 2021
Available online 1 May 2021
includes the synthesis of isoxazoline N-oxides from
mediated by the silyl triflate/triethylamine system.
a
-halonitroalkenes and subsequent dehydration
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoles
Nitronates
Silylation
[4+1]-Annulation
Introduction
warfare agents.[10] From a synthetic point of view their use is
mostly limited to the reaction with terminal acetylenes and the
preparation of 4–unsubstituted isoxazoles. For internal acetylenes
regioisomeric mixtures were observed, [5c,d] thus requiring the
development of indirect synthetic routes [5e].
Isoxazole derivatives represent an important class of hetero-
cyclic compounds for organic chemistry. They are useful interme-
diates in the synthesis of various amino-carbonyl compounds,
amino alcohols, as well as other heterocycles such as pyrroles or
oxazepines.[1] Additionally, the isoxazole core is a common hete-
rocyclic scaffold in the design of bioactive molecules. The various
bioactivities of isoxazole derivatives makes them promising targets
for drug development and crop protection (Fig. 1).[2] Of special
interest are 3-halo-substituted derivatives, as the presence of a
good leaving group (halogen) allows binding to the biomolecules
via nucleophilic displacement reactions.[3] Besides medicinal
applications their usefulness is highlighted in several total synthe-
ses of alkaloids.[4]
Two of the most common routes toward 3-haloisoxazoles uti-
lize the corresponding dihaloformaldoximes (phosgene oximes)
as starting materials (Scheme 1).[5,6,7] Under basic conditions
they are converted to halonitrile oxides that further undergo
[3 + 2]-cycloaddition with alkynes.[5] Alternatively, their reaction
with metal acetylides is employed.[6] Other approaches include
treatment of isoxazolones with POCl3[8] and acidic cyclization of
b-nitroketones.[9] Despite numerous literature examples, the use
of dihaloformaldoximes has several drawbacks. One limitation is
associated with their hazardous nature and consideration as
Results and discussion
We envisaged that fully substituted 3-haloisoxazoles 3 could be
obtained from a–halonitroalkenes 1 via a [4 + 1]-annulation route
as depicted in Scheme 1. This required reaction with sulfur ylides
and subsequent dehydration of N-oxides 2. Such an approach
should eliminate regioselectivity issues present in the [3 + 2]-
route. Although the first step is rather well-developed it was poorly
described for the preparation of 3-halo-substituted N–oxides.
[11,12] A priori, two main reaction pathways could be expected
(Scheme 2). Thus, initial Michael addition should lead to interme-
diate A that can undergo ring closure via intramolecular substitu-
tion of the sulfide with a nitronate anion. Here O-attack results
in the target isoxazoline N-oxide, while C-attack results in the
cyclopropane derivative. Indeed, we have previously observed
side-processes of cyclopropane formation during the annulation
of
a–fluoronitroalkenes.[13] Gratifyingly, the reaction of model
chloronitroalkene 1a produced the expected N-oxide 2a in 88%
yield and no cyclopropane formation was observed. This can be
attributed to steric hindrance provided by the large halogen pre-
venting C–attack. Having the N-oxide 2a in hand we moved to
the next step, namely, transformation of the N–oxide into the
⇑
Corresponding author.
E-mail addresses: tabolin87@mail.ru, atabolin@ioc.ac.ru (A.A. Tabolin).
https://doi.org/10.1016/j.tetlet.2021.153106
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

A.A. Fadeeva, S.L. Ioffe and A.A. Tabolin
Tetrahedron Letters 73 (2021) 153106
Scheme 3. Proposed dehydration of N-oxide 2a under various conditions.
Figure 1. Representative examples of bioactive isoxazole derivatives.
Thus, various electrophilic agents were tested (SOCl2/DIPEA,
AcCl/NEt3, t-BuC(O)Cl/NEt3, BzCl/NEt3, TMSBr/NEt3, TMSOTf/
NEt3). The silylation conditions (TMSOTf/NEt3) both left the 3–
halosubstituent intact and gave the target isoxazole 3a in good
yield (67%).
With conditions in hand we proceeded to evaluate the reaction
scope. Various readily available chloro- and bromo-nitroalkenes 1
[15] were reacted with sulfur ylides producing N-oxides 2 (Table 1).
[16] However, these 3-halogen-derivatives 2 turned out to be less
stable than the corresponding 3–alkyl-substituted analogs. In
numerous cases isoxazoline N-oxides 2 were isolated as oils and
shortly turned green. 1H NMR spectroscopy also showed their
decay into unknown products. Therefore N–oxides 2 were subse-
quently dehydrated without prolonged storage. Good yields were
achieved for electron-donating (p-OMe, 3a,b), neutral (p-Hal, 3c-
f) and electron-withdrawing (p-CO2Me, 3g,h) substituted aromat-
ics. However, poor yields were observed for o-substituted products
3l,m. Aromatic substituents at C4 significantly influenced the
[4 + 1]-annulation reaction. When aliphatic nitroalkenes were
used, N-oxides 2n,o were obtained in rather low yields. Moreover,
chloro-substituted N–oxide 2n produced the corresponding isoxa-
zole 3n in good yield, while bromo-derivative 2o gave mostly
decomposition products. 4–Aryl-5-unsubstituted isoxazole 3p is
particularly notable, since such structures are difficult to obtain
by conventional methods due to the regiochemical issues of
[3 + 2]-cycloaddition (see Scheme 1). Also, the good yield of 3p
demonstrated that the presence of a carboxylate group at C5 is
not necessary for successful abstraction of C5–H and elimination
of TMSOH (see mechanism, Scheme 2). Unfortunately, 5-benzoyl-
substituted isoxazoline-N–oxide 2q gave a poor yield of the corre-
sponding isoxazoline, that can be attributed to silylation of the
keto-group. The structures of the obtained products were sup-
ported by 1H and 13C NMR (including 2D) spectroscopy as well as
by HRMS data.
Scheme 1. Approaches toward 3-haloisoxazoles.
Further transformations were performed to show the synthetic
utility of products 3 (Scheme 4). Thus, alkaline hydrolysis of 3a
resulted in selective saponification of the ester group leaving the
3–halogen-substituent intact.[17] Similarly, the ester group could
be converted to amide 5 [18]. Modification of the aryl group was
accomplished via Suzuki coupling of substrate 3e with p–methox-
yphenyl boronic acid.
Scheme 2. Reaction of nitroalkene 1a with a sulfur ylide.
isoxazole (Scheme 3). However, traditional basic conditions[14]
(DBU, NEt3) applied to substrate 2a did not give the desired
chloroisoxazole since no halogen was observed by MS-data. This
result may be attributed to the elimination of chloride from oxi-
mate-anion B produced by abstraction of hydrogen at C5. In order
to avoid anionic intermediates we pursued another mode of dehy-
dration. We proposed that electrophile (E+) addition and proton
abstraction at C4 could lead to 2H-isoxazolidine C, which in turn
could undergo elimination of EOH furnishing the target isoxazole.
Conclusion
In conclusion, a new approach toward polysubstituted 3–
haloisoxazoles starting from nitroalkenes was developed. The key
step of the sequence is the silyl triflate mediated dehydration of
isoxazoline N-oxides that better tolerated labile halogen sub-
stituents compared to classical basic literature conditions. Good
2

A.A. Fadeeva, S.L. Ioffe and A.A. Tabolin
Tetrahedron Letters 73 (2021) 153106
Table 1
Synthesis of 3-haloisoxazoles 3 from nitroalkenes 1 via N-oxides 2.
2,3
R1
R2
Hal
Yield 2 (%)
Yield 3 (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
4-MeOC6H4-
4-MeOC6H4-
4-ClC6H4-
4-ClC6H4-
4-BrC6H4-
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
Br
Cl
Br
Cl
Cl
88
89
93
68
quant.
39
70
38
94
57
91
66
60
36
23
12
57
67
61
48
40
52
56
50
42
75
44
32
13
8
4-BrC6H4-
4-(CO2Me)C6H4-
4-(CO2Me)C6H4-
3,4-(OCH2O)C6H3-
3,4-(OCH2O)C6H3-
3-Br-4-MeOC6H3-
2-BrC6H4-
2-BrC6H4-
PhCH2CH2-
PhCH2CH2-
4-MeOC6H4-
4-MeOC6H4-
77
<20a
78
12
PhCO
a
could not be separated from impurities
Acknowledgments
This work was supported by the Russian Science Foundation
(grant 19-73-00146). The authors thank Dr. N. G. Kolotyrkina and
Dr. A. O. Chizhov (N. D. Zelinsky Institute of Organic Chemistry)
for registration of HRMS.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153106.
References
[1] (a) P.G. Baraldi, A. Barco, S. Benetti, G.P. Pollini, D. Simoni, Synthesis (1987)
857–869, https://doi.org/10.1055/s-1987-28105;
(b) L. Li, T.-D. Tan, Y.-Q. Zhang, X. Liu, L.-W. Ye, Org. Biomol. Chem. 15 (2017)
8483–8492, https://doi.org/10.1039/C7OB01895A;
(c) F. Hu, M. Szostak, Adv. Synth. Catal. 357 (2015) 2583–2614, https://doi.org/
10.1002/adsc.201500319.
[2] (a) J. Zhu, J. Mo, H.-z. Lin, Y. Chen, H-p. Sun, Bioorg. Med. Chem. 26 (2018)
3065-3075. DOI: 10.1016/j.bmc.2018.05.013; (b) A. Sysak, B. Obminska-
Mrukowicz, Eur. J. Med. Chem. 137 (2017) 292-309. DOI: 10.1016/j.
ejmech.2017.06.002; (c) J.N. Pairas, F. Perperopoulou, P.G. Tsoungas, G.
Varvounis,
ChemMedChem.
12
(2017)
408-419.
DOI:
10.1002/
Scheme 4. Modifications of isoxazoles 3.
cmdc.201700023; (d) C. Lamberth, J. Heterocyclic Chem. 55 (2018) 2035-
2045. DOI: 10.1002/jhet.3252.
[3] (a) A. Pinto, L. Tamborini, G. Cullia, P. Conti, C. De Micheli, ChemMedChem 11
(2016) 10–14, https://doi.org/10.1002/cmdc.201500496;
yields of the target products were achieved and subsequent selec-
tive transformations were demonstrated.
(b) O.B. Bondarenko, N.V. Zyk, Chem. Heterocyclic Comp. 56 (2020) 1523–
1534, https://doi.org/10.1007/s10593-020-02845-8 [Khim. Geterotsikl. Soed.
56 (2020) 1523-1534].
[4] (a) L. Leng, X. Zhou, Q. Liao, F. Wang, H. Song, D. Zhang, X.-Y. Liu, Y. Qin, Angew.
Chem. Int. Ed. 56 (2017) 3703-3707. DOI: 10.1002/anie.201700831 [Angew.
Chem. 129 (2017) 3757-3761. DOI: 10.1002/ange.201700831]; (b) H.-X.
Huang, S.-J. Jin, J. Gong, D. Zhang, H. Song, Y. Qin, Chem. Eur. J. 21 (2015)
13284-13290. DOI: 10.1002/chem.201502011; (c) Y. Yoshii, H. Tokuyama, D.Y-
K. Chen, Angew. Chem. Int. Ed. 56 (2017) 12277-12281. DOI: 10.1002/
anie.201706312 [Angew. Chem. 129 (2017) 12445-12449. DOI: 10.1002/
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
3

A.A. Fadeeva, S.L. Ioffe and A.A. Tabolin
Tetrahedron Letters 73 (2021) 153106
ange.201706312]; (d) C. Ebner, E. M. Carreira, Angew. Chem. Int. Ed. 54 (2015)
11227-11230. DOI: 10.1002/anie.201505126 [Angew. Chem. 127 (2015)
11379-11382. DOI: 10.1002/ange.201505126]; (e) M. G. Kociolek, N. G.
Straub, J. V. Schuster, Synlett (2005) 259-262. DOI: 10.1055/s-2004-837216.
[5] (a) D. Chiarino, M. Napoletano, A. Sala, J. Heterocyclic Chem. 24 (1987) 43–46,
https://doi.org/10.1002/jhet.5570240109;
[13] V.A. Motornov, A.A. Tabolin, R.A. Novikov, Y.V. Nelyubina, V.G. Nenajdenko, S.L.
Ioffe, Org. Chem. Front.
C8QO00623G.
5 (2018) 2588–2594, https://doi.org/10.1039/
[14] Review: (a) A.A. Tabolin, S.L. Ioffe, Chem. Rev. 114 (2014) 5426-5476. DOI:
10.1021/cr400196x; Selected seminal publications: (b) A.S. Maksimenko, V.P.
Kislyi, N.B. Chernysheva, Yu.A. Strelenko, Y.V. Zubavichus, V.N. Khrustalev, M.N.
Semenova, V.V. Semenov, Eur. J. Org. Chem. (2019) 4260-4270. DOI: 10.1002/
ejoc.201900643; (c) N.B. Chernysheva, A.S. Maksimenko, F.A. Andreyanov, V.P.
Kislyi, Yu.A. Strelenko, V.N. Khrustalev, M.N. Semenova, V.V. Semenov, Eur. J.
Med. Chem. 146 (2018) 511-518. DOI: 10.1016/j.ejmech.2018.01.070; (d) E.
Kaji, S. Zen, Chem. Pharm. Bull. 28 (1980) 479-486. DOI: 10.1248/cpb.28.479; (e)
A.Yu. Smirnov, E.R. Zaitseva, O.A. Belozerova, R.S. Alekseyev, N.S. Baleeva, M.B.
Zagudaylova, A.A. Mikhaylov, M.S. Baranov, J. Org. Chem. 84 (2019) 15417-
15428. DOI: 10.1021/acs.joc.9b02427.
(b) D. Chiarino, M. Napoletano, A. Sala, Synth. Commun. 18 (1988) 1171–1176,
https://doi.org/10.1080/00397918808060905;
(c) P. Pevarello, R. Amici, M. Colombo, M. Varasi, J. Chem. Soc., Perkin Trans. 1
(1993) 2151–2152, https://doi.org/10.1039/P19930002151;
(d) F. Farina, M.T. Fraile, M.R. Martin, M.V. Martin, A.M. de Guerenu,
Heterocycles 40 (1995) 285–292, https://doi.org/10.3987/COM-94-S27;
(e) J.E. Moore, K.M. Goodenough, D. Spinks, J.P.A. Harrity, Synlett (2002) 2071–
2073, https://doi.org/10.1055/s-2002-35595.
[6] (a) W. Chen, B. Wang, N. Liu, D. Huang, X. Wang, Y. Hu, Org. Lett. 16 (2014)
6140–6143, https://doi.org/10.1021/ol503008t;
[15] (a) A.S. Fadeeva, S.L. Ioffe, A.A. Tabolin, Synthesis 52 (2020) 2679–2688,
https://doi.org/10.1055/s-0040-1707396;
(b) W. Chen, J. Zhang, B. Wang, Z. Zhao, X. Wang, Y. Hu, J. Org. Chem. 80 (2015)
2413–2417, https://doi.org/10.1021/jo502634h;
(b) D. Dauzonne, P. Demerseman, Synthesis (1990) 66–70, https://doi.org/
10.1055/s-1990-26791;
(c) P. Bravo, G. Gaudiano, A. Quilico, A. Ricca, Gazz. Chim. Ital. 91 (1961) 47–
64.
(c) M. Ganesh, I.N.N. Namboothiri, Tetrahedron 63 (2007) (1983) 11973–
11981, https://doi.org/10.1016/j.tet.2007.09.012;
[7] S. V. Kovalenko, V. I. Gorin, I. V. Martynov, Bull. Acad. Sci. USSR Div. Chem. Sci.
38 (1989) 1335. DOI: 10.1007/BF00957202 [Izv. Akad. Nauk SSSR Ser. Khim.
(1989) 1454].
[8] G. Schlewer, P. Krogsgaard-Larsen, Acta Chem. Scand. B. 38 (1984) 815–819,
https://doi.org/10.3891/acta.chem.scand.38b-0815.
[9] R. Fusco, S. Rossi, Chem. Ind. (London) (1957) 1650. b) J. Thiele, H. Landers,
Liebigs Ann. Chem. 369 (1909) 300-310. DOI: 10.1002/jlac.19093690305.
[10] C. Battilocchio, F. Bosica, S.M. Rowe, B.L. Abreu, E. Godineau, M. Lehmann, S.V.
Ley, Org. Process Res. Dev. 21 (2017) 1588–1594, https://doi.org/10.1021/acs.
oprd.7b00229.
(d) S.-W. Yu, S.-H. Zhao, H. Chen, X.-Y. Xu, W.-C. Yuan, X.-M. Zhang,
ChemistrySelect 3 (2018) 4827–4830, https://doi.org/10.1002/slct.201800396.
[16] The relative 4,5-trans-configuration of isoxazoline N-oxides 2 was assigned
based on the coupling constant between C4–H and C5–H (J = 3.9-5.8 Hz). cf,
e.g. (a) Ya. A. Naumovich, V. E. Buckland, D. A. Sen’ko, Yu. V. Nelyubina, Yu. A.
Khoroshutina, Yu. A. Khoroshutina, A. Yu. Sukhorukov, S. L. Ioffe, Org. Biomol.
Chem. 14 (2016) 3963-3974. DOI: 10.1039/c6ob00388e; (b) C.-Y. Zhu, X.-L.
Sun, X.-M. Deng, J.-C. Zheng, Y. Tang, Tetrahedron 64 (2008) 5583-5589. DOI:
10.1016/j.tet.2008.03.075; (c) R. Sustmann, R. Huisgen, H. Huber, Chem. Ber.
100 (1967) 1802-1813. DOI: 10.1002/cber.19671000605.
[11] A.A. Tabolin, A.Y. Sukhorukov, S.L. Ioffe, A.D. Dilman, Synthesis 49 (2017)
3255–3268, https://doi.org/10.1055/s-0036-1589063.
[17] S. Jin, X. Sun, D. Liu, H. Xie, Y. Rao, Chemical Papers 73 (2019) 1333–1345,
https://doi.org/10.1007/s11696-019-00686-0.
[12] N.N. Magdesieva, T.A. Sergeeva, R.A. Kyandzhetsian, J. Org. Chem. USSR 21
(1985) 1813-1815 [Zhurn. Org. Khim. 21 (1985) 1980-1983.]
[18] M. Girardin, S.J. Dolman, S. Lauzon, S.G. Ouellet, G. Hughes, P. Fernandez, G.
Zhou, P.D. O’Shea, Org. Process Res. Dev. 15 (2011) 1073–1080, https://doi.org/
10.1021/op200186d.
4