A one-pot approach to Δ2-isoxazolines from ketones and arylacetylenes

Article abstract of DOI:10.1021/ol303132u

The sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBut/DMSO followed by the treatment of the reaction mixture with H₂O and KOH leads to Δ²-isoxazolines in up to 88% yield.

Full text of DOI:10.1021/ol303132u

ORGANIC
LETTERS
A One-Pot Approach to Δ2‑Isoxazolines
from Ketones and Arylacetylenes
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Vol. XX, No. XX
000–000
Elena Yu. Schmidt, Inna V. Tatarinova, Elena V. Ivanova, Nadezhda V. Zorina,
Igor’ A. Ushakov, and Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch,
Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia
boris_trofimov@irioch.irk.ru
Received November 14, 2012
ABSTRACT
The sequential reaction of ketones with arylacetylenes and hydroxylamine in the presence of KOBut/DMSO followed by the treatment of the
reaction mixture with H2O and KOH leads to Δ2-isoxazolines in up to 88% yield.
The Δ2-isoxazoline structural unit is a frequently met
active pharmacophore in numerous biologically important
molecules including those possessing antifungal,1 anti-
bacterial,2 antitubercular,3 siderophore,4 antidepressant,5
and β-galactosidase inhibiting properties.6 Some of them
exhibit promising antiviral activity, e.g. toward hepatitis A
and herpes.7 Generally, Δ2-isoxazolines are recognized as
valuable building blocks in organic synthesis,8 particularly as
chiral ligands.9 Along this line, they are readily convertible
into diverse key synthetic structures such as β-amino
acids,10 β-hydroxy nitriles,11 and β-hydroxy ketones.12 The
high reactivity of the NÀO bond paves a short and easy route
to pharmaceutically rewarding γ-aminoalcohols, known
for their antitubercular activity.13 Δ2-Isoxazolines are also
applied in the synthesis of natural products.14 No wonder,
the building up of a Δ2-isoxazoline moiety invokes ever-
growing synthetic efforts.
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34, 8465. (b) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587.
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Ed. 2001, 40, 2082. (d) Jiang, D.; Chen, Y. J. Org. Chem. 2008, 73, 9181.
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V.; Schroter, D. Synthesis 1990, 556. (c) Frederickson, M. Tetrahedron
1997, 53, 403. (d) Saha, A.; Bhattacharjya, A. Chem. Commun. 1997, 495.
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2001, 3, 727. (f) Scott, J. P.; Oliver, S. F.; Brands, K. M. J.; Brewer, S. E.;
Davies, A. J.; Gibb, A. D.; Hands, D.; Keen, S. P.; Sheen, F. J.; Reamer,
R. A.; Wilson, R. D.; Dolling, U. J. Org. Chem. 2006, 71, 3086.
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G. F. J. Org. Chem. 1984, 49, 4595. (b) Torssell, K. B. G. Nitrile Oxides,
Nitrones, and Nitronates in Organic Chemistry; VCH: Stuttgart, Germany,
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2008, 12, 1.
r
10.1021/ol303132u
XXXX American Chemical Society

Commonly, isoxazoline derivatives are constructed
by 1,3-dipolar cycloaddition of alkenes to nitrile oxides
generated in situ by dehydration of nitro compounds15
or dehydrogenation of oximes.3b,15a,15b,16 3-Acetyl- and
3-benzoyl isoxazolines were synthesized by the reaction of
alkenes with acetone or acetophenone in the presence of
formed as E,E isomers, while alkylaryl ketones are oxi-
mated to Z,E isomers (such as 4c,d), also stereoselectively.
(NH4)2Ce(NO3)6 or (NH4)2Ce(NO3)5 4H2O17 involving
3
the intermediate nitro ketones which were further oxidized
to the nitrile oxides. Δ2-Isoxazolines are also formed via
base-catalyzed or catalyst-free cyclization of R,β-unsaturated
ketones with hydroxylamine.2,7,18 Isoxazolinylacetates were
synthesized from oximes of β,γ-unsaturated ketones by
their palladium-mediated nucleometalation/methoxycar-
bonylation.19 The same oximes when subjected to palladium-
catalyzed [Pd(dba)3/phosphine/NaOBut] carboetherifi-
cation together with arylbromides gave 3-aryl-5-benzyl
Δ2-isoxazolines.20
Oximes 4aÀd do readily cyclize to the corresponding
Δ2-isoxazolines thus confirming the easy isomerization of
both the oxime (for oximes of E,E configuration) and
β,γ-ethylenic moiety as the above rationale suggests.
As seen from Table 1, this strategy is effective for a great
diversity of ketones 1 such as dialkyl (entries 1À4),
cycloalkyl (entries 5À7), and alkylaryl (entries 8À15), as
well as for a variety of arylacetylenes. Acylated condensed
aromatics (entry 14) and fluorine derivatives (both ketones
and acetylenes) fairly tolerate the reaction conditions and
also afford the desired products in good yields (entries 10,
11, 13), thus proving the generality of the strategy elabo-
rated. The variable yields appear to be indicative of the fact
that as shown above the overall process involves at least
five separate mechanistic steps (Scheme 1): addition of
ketones to arylacetylenes, oximation of the resulted
β,γ-unsaturated ketones, E f Z isomerization of the oximes
(for oximes of alkyl- and cycloalkyl ketones), prototropic
rearrangement of oximes of β,γ-unsaturated ketones
to oximes of R,β-unsaturated ketones, and their final
cyclization.
The synthetic meaning of the strategy developed is aug-
mented by the fact that it allows preparation of 5-benzyl
Δ2-isoxazolines. Theinterestinthe latterisgrowing rapidly
because they are activeagainst Mycobacterium tuberculosis
H37Ra and H37Rv3b and possess antistress activity in
acute stress (AS) induced peripheral changes.16 Also, they
activate both estrogen receptor R and β (ERR, ERβ).22
Currently, 5-benzyl-3-phenyl Δ2-isoxazolines are synthe-
sized by the traditional methods, e.g. hetero-DielsÀ
Alder reactions of aromatic aldoximes with alkenes.3b,16,22
Here we report a new general one-pot strategy for the
synthesis of 5-benzyl Δ2-isoxazolines 3 from ketones 1 and
arylacetylenes 2 (Table 1).
The overall reaction is implemented as follows: to the
mixture of ketone 1 and arylacetylene 2 in the KOBut/
DMSO system, kept at 100 °C for 30 min, water and
hydroxylamine hydrochloride areadded at70°C, and after
1.5À3.5 h the reaction mixture is treated with KOH at the
same temperature (70 °C) for 30 min.
Apparently, the assembly of Δ2-isoxazolines 3 comprises
the following key steps (Scheme 1): the potassium dieno-
lates A, the adducts of ketones to arylacetylenes,21 react
with NH2OH HCl to give the oximes of β,γ-unsaturated
3
ketones C (via the intermediate formation of the corre-
sponding ketones B) undergoing the final ring closure,
likely via the preliminary prototropic rearrangement to
oximes of the corresponding (Z)-R,β-unsaturated ketones D.
Scheme 1. Plausible Key Steps of One-Pot Assembly of 5-Benzyl
Δ2-Isoxazolines 3 from Ketones 1, Acetylenes 2, and
Hydroxylamine
(16) Maurya, R.; Ahmad, A.; Gupta, P.; Chand, K.; Kumar, M.;
Jayendra; Rawat, P.; Rasheed, N.; Palit, G. Med. Chem. Res. 2011, 20,
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(17) Itoh, K.; Takahashi, S.; Ueki, T.; Sugiyama, T.; Takahashic,
T. T.; Horiuchia, C. A. Tetrahedron Lett. 2002, 43, 7035.
(18) (a) Sinisterra, J. V.; Marinas, J. M. Bull. Soc. Chim. Belg. 1987,
96, 293. (b) Norman, A. L.; Shurrush, K. A.; Calleroz, A. T.; Mosher,
M. D. Tetrahedron Lett. 2007, 48, 6849. (c) Jadhav, S. B.; Shastri, R. A.;
Gaikwad, K. V.; Gaikwad, S. V. E-J. Chem. 2009, 6, S183. (d) Mohane,
S. R.; Thakare, V. G.; Berad, B. N. Asian J. Chem. 2009, 21, 7422.
(19) Mosher, M. D.; Emmerich, L. G.; Frost, K. S.; Anderson, B.
J. Heterocycl. Chem. 2006, 43, 535.
(20) Jiang, D.; Peng, J.; Chen, Y. Org. Lett. 2008, 10, 1695.
(21) (a) Trofimov, B. A.; Schmidt, E. Yu.; Ushakov, I. A.; Zorina,
N. V.; Skital’tseva, E. V.; Protsuk, N. I.; Mikhaleva, A. I. Chem.;Eur.
J. 2010, 16, 8516. (b) Trofimov, B. A.; Schmidt, E. Yu.; Zorina, N. V.;
Ivanova, E. V.; Ushakov, I. A. J. Org. Chem. 2012, 77, 6880.
(c) Trofimov, B. A.; Schmidt, E. Yu.; Zorina, N. V.; Ivanova, E. V.;
Ushakov, I. A.; Mikhaleva, A. I. Adv. Synth. Catal. 2012, 354, 1813.
(22) Pulkkinen, J. T.; Honkakoski, P.; Peraekulae, M.; Berezi, I.;
Laatikainen, R. J. Med. Chem. 2008, 31, 3562.
This rationale has been proven by the synthesis of
oximes C (4aÀd) from (E)-β,γ-unsaturated ketones B,
isolated from the reaction mixture under the same condi-
tions, and hydroxylamine hydrochloride. The oximes of
dialkyl and cycloalkyl ketones (such as 4a,b) are selectively
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. One-Pot Synthesis of 5-Benzyl Δ2-Isoxazolines 3 from Ketones 1 and Arylacetylenes 2a
a Reagents and conditions: (1) ketone 1 (5 mmol), arylacetylene 2 (5 mmol), KOBut (6 mmol), DMSO (10 mL), 100 °C, 30 min; (2) H2O
(5 mmol), NH2OH HCl (6 mmol), 70 °C, 1.5À3.5 h; (3) KOH (5 mmol), 70 °C, 30 min. b Isolated yield after column chromatography or
3
recrystallization.
Org. Lett., Vol. XX, No. XX, XXXX
C

Therefore, involving other readily available starting mate-
rials such as ketones and arylacetylenes for the synthesis of
5-benzyl Δ2-isoxazolines contributes considerably to their
accessibility and structural variety.
In conclusion, a one-pot general strategy for the synthe-
sis of 5-benzyl Δ2-isoxazolines, synthetically and pharma-
ceutically important heterocycles, from ketones, arylacety-
lenes, and hydroxylamine has been developed. The
strategy is applicable for the preparation of 5-benzyl
Δ2-isoxazolines with both aliphatic and aromatic sub-
stituents at C-3 of the isoxazoline ring due to the great
variety of starting ketones controlling these substitu-
ents’ structures.
Acknowledgment. This work was financially supported
by the Russian Foundation of Basic Research (Grant
11-03-00270).
Supporting Information Available. Experimental pro-
cedure, characterization data, and copies of spectra for all
new compounds. This material is available free of charge
via Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX