Green organocatalytic synthesis of isoxazolines via a one-pot oxidation of allyloximes

Article abstract of DOI:10.1021/acs.orglett.6b03380

A green, sustainable, organocatalytic, and efficient synthesis of isoxazolines from allyloximes was developed. A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes, utilizing H₂O₂ as the green oxidant, was taken advantage of in order to introduce a cheap and environmentally friendly protocol for the synthesis of substituted isoxazolines. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b03380

Letter
pubs.acs.org/OrgLett
Green Organocatalytic Synthesis of Isoxazolines via a One-Pot
Oxidation of Allyloximes
Ierasia Triandafillidi and Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis,
Athens 15771, Greece
S
* Supporting Information
ABSTRACT: A green, sustainable, organocatalytic, and efficient synthesis of isoxazolines from allyloximes was developed. A
2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes, utilizing H2O2 as the green oxidant, was taken advantage of in
order to introduce a cheap and environmentally friendly protocol for the synthesis of substituted isoxazolines. A variety of
substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in moderate to excellent
yields.
soxazolines and the corresponding unsaturated analogues,
isoxazoles, constitute very useful and versatile scaffolds in
to that of the marketed drug Zyvox.4 From a variety of simple
molecules having the isoxazoline scaffold as the key structural
backbone, ISO-1 was identified as a remarkable MIF antagonist
exhibiting remarkable antidiabetic activity.5 Along the same
lines, another simple isoxazoline derivative has been recently
identified as a very highly potent DNA methyltransferase 1
inhibitor (Figure 1).6 In addition, the corresponding unsatu-
rated analogue, the isoxazole moiety, constitutes an important
pharmacophore in medicinal chemistry, since it is extensively
found in many marketed drugs, such as valdecoxib and
parecoxib, which are used as nonsteroidal anti-inflammatory
drugs treating osteoarthritis, rheumatoid arthritis, and menstru-
al symptoms,7 or cloxacillin and related compounds (oxacillin
and flucloxacillin), which are widely used clinically against
infections caused by penicillin-resistant Staphylococcus aureus
(Figure 1).8
I
modern organic chemistry that can be found in a plethora of
complex natural products and in numerous molecules of
biological importance. Compounds bearing the isoxazoline
moiety have been described to exhibit impressive anti-
inflammatory,1 antifungal,2 antimicrobial,3 and antibacterial4
activity (Figure 1). For example, the top left isoxazoline
compound in Figure 1 exhibits a medicinal profile very similar
Putting aside their pharmacophore nature, isoxazolines are
also useful in organic synthesis as precursors for the production
of β-hydroxy ketones9 and 1,3-diols,10 which are present in
numerous natural products.
As a consequence of their synthetic utility, a plethora of
synthetic approaches have been devised for the synthesis of
isoxazolines (Scheme 1). The most common synthetic
approach to isoxazolines constitutes cycloaddition reactions,11
with the 1,3-dipolar cycloaddition of nitrile oxides with alkenes
having the lion’s share.11a−e Alternatively, one can envisage the
cyclization of allyl oximes to lead to substituted isoxazolines
(Scheme 1). In this context, oxidative cyclization of allyloximes
has been achieved by employing a variety of metal catalysts
Figure 1. Representative bioactive molecules containing the isoxazo-
line or the isoxazole group.
Received: November 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03380
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Letter
Scheme 1. Synthetic Approaches for the Synthesis of
Isoxazolines
Table 1. Optimization of the Reaction Conditions for the
Synthesis of Isoxazolines from Allyloximes
a
b
entry catalyst (mol %) MeCN/H2O2 (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
0
12
12
16
16
16
16
16
16
16
16
t-BuOH
t-BuOH
t-BuOH
MeCN
EtOAc
MeOH
THF
28
5
20
20
20
20
20
20
20
20
76
74
75
12
38
40
78
73
CHCl3
t-BuOH
t-BuOH
c
d
10
a
All reactions were carried out with 1a (0.30 mmol), 2,2,2-trifluoro-1-
phenylethanone, solvent (0.6 mL), aqueous buffer solution (0.6 mL,
0.6 M K2CO3−4 × 10−4 M EDTA disodium salt), acetonitrile, and
30% aqueous H2O2. The reaction mixture was allowed to stir for 18 h.
b
c
d
Isolated yield. t-BuOH (0.3 mL), aq buffer (0.3 mL). t-BuOH (1.2
mL), aq buffer (1.2 mL).
forming isoxazoline 2a, albeit in low yield. However, no
additional heating or additives are required for this one-pot
transformation to occur. If the catalyst is omitted, traces of the
product are observed (Table 1, entry 2). By increasing the
catalyst loading to 20 mol % and the equivalents of the oxidant,
the product could be isolated in high yield (Table 1, entry 3).
Further optimization regarding the organic solvent did not lead
to higher yield (Table 1, entries 4−8). Subtle changes in the
reaction concentration led to the highest yield of the
isoxazoline 2a (Table 1, entries 9 and 10).
Having in hand the optimum reaction conditions, we focused
on exploring the substrate scope of this new green and
sustainable protocol (Scheme 2). Initially, a number of
substituted aromatic allyloximes (1a−i) were utilized (Scheme
2). In all cases, the products were isolated in high to excellent
yields. Various substitution patterns with different electron-rich
and electron-poor substituents were well tolerated. In addition,
starting from isoxazoline 2i and following literature proce-
dures,6 the DNA methyltransferase 1 inhibitor of Figure 1 was
synthesized following a two-step reaction sequence. Next, a
series of bulky α-substituted aliphatic allyloximes were prepared
and tested, affording the desired isoxazolines 2j−m in moderate
to high yields. When the aromatic moiety was replaced by an
aliphatic chain, the yield remained at high levels (Scheme 2,
compounds 2n−q). It must be mentioned that additional
functional groups as protected alcohols and aromatics can be
well tolerated. In an effort to push the limits of the
methodology and test more hindered classes of substrates, a
number of alkenes were tested. Disubstituted alkene 1r afforded
the corresponding isoxazoline in excellent yield, affording a
tetrasubstituted carbon in the final product. Finally, trisub-
stituted isoxazolines, like 2s, can be prepared by this
methodology in excellent yield; however, a mixture of
diastereomers is observed. Furthermore, 1,2-disubstituted or
such as palladium,5,12 copper,13 or cobalt14 (Scheme 1, B).
Despite the widespread popularity of these reactions, the
toxicity of metals and high levels of inorganic waste make their
application harmful for the environment. A few metal-free
methods for the synthesis of isoxazolines have been reported
using either stoichiometric radical pathways (TEMPO-medi-
ated, hypervalent iodine-, or TBN-mediated processes)9b,15 or
organocatalysts (thioureas or TBAI) (Scheme 1, path D).16
However, as strange as it may seem, to our knowledge there is
no report (stoichiometric or catalytic) in the literature for the
in situ epoxidation of allyloximes followed by C−O cyclization
to the desired isoxazoline via the intramolecular ring opening of
the epoxide (Scheme 1, bottom).
We have been actively involved in the field of organocatalysis
and very recently reported a cheap, green, and environmentally
friendly protocol for various oxidations employing H2O2 as the
green oxidant, whose only byproduct is water with 2,2,2-
trifluoroacetophenone as the organocatalyst.17 We envisaged
we could extend this organocatalytic oxidative protocol via the
introduction of an one-pot procedure for the isolation of
isoxazolines. We postulated that once the intermediate epoxide
is formed, an intramolecular ring opening reaction of the in situ
prepared epoxide would afford the desired cyclized compound
bearing a hydroxy moiety. Although the hydroxy group can be
easily transformed to a variety of functional groups, there are
only sparse reports for the synthesis of isoxazolines bearing this
group.11f,12a,14
Our study began by employing the optimum reaction
conditions for the epoxidation of terminal alkenes (Table 1,
entry 1).17c Starting from allyloxime 1a, the direct synthesis of
isoxazolines is demonstrated. Initially, the epoxide is formed as
the intermediate, and once the optimal pH is utilized (pH =
11), the hydroxy group of the oxime ring opens the epoxide,
B
DOI: 10.1021/acs.orglett.6b03380
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40% of the all-cis epoxide. This can be easily explained by the
propensity of the trans-diastereomer (where epoxide and oxime
moieties are away) to cyclize, while the cis-diastereomer (where
epoxide and oxime moieties are in the same side, all cis) is
unable to perform such a transformation. In addition, in some
cases where the alkene moiety is placed one carbon atom
further away from the oxime, like in oxime 1w, the literature
reports a failure for the reaction to take place.14 In our case,
when oxime 1w was subjected to the reaction conditions, the
epoxidation occurred. In order to ensure cyclization, DBU was
added in situ to afford the six-membered product 2w (which is
a dihydro-1,2-oxazine) in a satisfactory yield.
Scheme 2. Substrate Scope of the One-Pot Organocatalytic
Oxidation of Allyloximes to Isoxazolines
In order to summarize the events that take place in this
protocol, a proposed reaction mechanism is shown in Scheme
4. Initially, the catalyst in the presence of the aqueous buffer
Scheme 4. Proposed Reaction Mechanism
affords diol I. Then, at the appropriate pH, MeCN reacts with
H2O2 to afford II, which in conjunction with H2O2 oxidizes I to
perhydrate IV.17 Another molecule of II reacts with IV and
affords the active oxidant of the protocol,18 which epoxides
allyloxime 1a. Then the deprotonated epoxyoxime (aqueous
buffer pH 11, pKa of oximes ∼11.3 in H2O) ring opens the
epoxide with simultaneous cyclization to isoxazoline 2a.
trisubstituted substrates were tested, affording the desired
products in good to excellent yields (2t,u).
In conclusion, a green, sustainable, and organocatalytic
protocol for the synthesis of isoxazolines from allyloximes was
developed. This synthetic approach utilizes a cheap and
commercially available metal-free organic molecule (2,2,2-
trifluoroacetophenone) as the catalyst and H2O2 as the green
oxidant and reports for the first time the one-pot epoxidation of
allyloximes followed by an in situ ring opening/cyclization
process leading to isoxazolines in good to excellent yields. The
substrate scope of the reaction is very general, since a variety of
aromatic and aliphatic substituted allyloximes bearing additional
functional groups can be well tolerated. Further substitution of
the allyl moiety can lead to polysubstituted isoxazolines, even
bearing tetrasubstituted carbon atoms. In addition, a preferred
cyclization approach was revealed for the synthesis of bicyclic
isoxazolines. Finally, allyloximes can be replaced by homoallylic
oximes leading to six-membered 1,2-oxazine derivatives. This
unprecedented, for this kind of transformation process was
made possible by simple addition of DBU followed by stirring
at room temperature. This novel approach of combining our
organocatalytic oxidation protocol in one-pot transformations
In an attempt to further expand the possibilities of this
protocol, additional substrates were prepared and tested with
interesting results (Scheme 3). Starting from allyloxime 1v, and
after the epoxidation reaction, a preferred cyclization took place
to afford the cyclized isoxazoline 2v in 40% yield, along with
Scheme 3. Additional Substrate Scope of the One-Pot
Organocatalytic Oxidation of Allyloximes to Isoxazolines
C
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7775. (c) Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11,
5394. (d) Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org.
Lett. 2011, 13, 2966. (e) Yoshimura, A.; Middleton, K. R.; Todora, A.
D.; Kastern, B. J.; Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Org.
Lett. 2013, 15, 4010. (f) Han, X.; Dong, L.; Geng, C.; Jiao, P. Org. Lett.
2015, 17, 3194. (g) Dong, L.; Geng, C.; Jiao, P. J. Org. Chem. 2015, 80,
10992.
(12) (a) Zhu, M.; Zhao, J.; Loh, T. J. Am. Chem. Soc. 2010, 132, 6284.
(b) Dong, K.-Y.; Qin, H.-T.; Liu, F.; Zhu, C. Org. Lett. 2014, 16, 5266.
(c) Dong, K.-Y.; Qin, H.-T.; Liu, F.; Zhu, C. Eur. J. Org. Chem. 2015,
2015, 1419.
(13) (a) He, Y.; Li, L.; Yang, Y.; Wang, Y.; Luo, J.; Liu, X.; Liang, Y.
Chem. Commun. 2013, 49, 5687. (b) Zhu, L.; Yu, H.; Xu, Z.; Jiang, X.;
Lin, L.; Wang, R. Org. Lett. 2014, 16, 1562.
(14) Li, W.; Jia, P.; Han, B.; Li, D.; Yu, W. Tetrahedron 2013, 69,
3274.
leading to products of high molecular complexity is currently
being pursued in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03380.
Experimental procedure, full optimization data, charac-
terization data, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ckokotos@chem.uoa.gr.
ORCID
(15) (a) Han, B.; Yang, X.; Fang, R.; Yu, W.; Wang, C.; Duan, X.;
Liu, S. Angew. Chem., Int. Ed. 2012, 51, 8816. (b) Zhu, X.; Wang, Y.-F.;
Ren, W.; Zhang, F.-L.; Chiba, S. Org. Lett. 2013, 15, 3214. (c) Peng,
X.; Deng, Y.; Yang, X.; Zhang, L.; Yu, W.; Han, B. Org. Lett. 2014, 16,
4650.
Christoforos G. Kokotos: 0000-0002-4762-7682
Notes
(16) (a) Tripathi, C. B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013,
52, 8450. (b) Yang, X.-L.; Chen, F.; Zhou, N.-N.; Yu, W.; Han, B. Org.
Lett. 2014, 16, 6476.
(17) (a) Limnios, D.; Kokotos, C. G. ACS Catal. 2013, 3, 2239.
(b) Limnios, D.; Kokotos, C. G. Chem. - Eur. J. 2014, 20, 559.
(c) Limnios, D.; Kokotos, C. G. J. Org. Chem. 2014, 79, 4270.
(d) Theodorou, A.; Limnios, D.; Kokotos, C. G. Chem. - Eur. J. 2015,
21, 5238. (e) Theodorou, A.; Kokotos, C. G. Green Chem. 2017,
DOI: 10.1039/C6GC02580C.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Operational Program “Educa-
tion and Lifelong Learning” for financial support through the
NSRF program “ENIΣXYΣH METAΔIΔAKTOPΩNEPEYN-
HTΩN” (PE 2431)” cofinanced by ESF and the Greek State.
(18) The structure of the active oxidant of the oxidation protocol is
still unknown, while the possibility of a dioxirane intermediate cannot
be ruled out.
REFERENCES
■
(1) (a) Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med. Chem.
2001, 44, 2921. (b) Basappa; Satish Kumar, M.; Nanjunda Swamy, S.;
Mahendra, M.; Shashidhara Prasad, J.; Viswanath, B. S.; Rangappa, K.
S. Bioorg. Med. Chem. Lett. 2004, 14, 3679.
(2) Basappa; Sadashiva, M. P.; Mantelingu, K.; Nanjunda Swamy, S.;
Rangappa, K. S. Bioorg. Med. Chem. 2003, 11, 4539.
(3) Priya, B. S.; Basappa; Rangappa, K. S. Heterocycl. Commun. 2006,
12, 35.
(4) Barbachyn, M. R.; Cleek, G. J.; Dolak, L. A.; Garmon, S. A.;
Morris, J.; Seest, E. P.; Thomas, R. C.; Toops, D. C.; Watt, W.;
Wishka, D. G.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R.
D.; Stapert, D.; Yagi, B. H.; Adams, W. J.; Friis, J. M.; Slatter, J. G.;
Sams, J. P.; Oien, N. L.; Zaya, M. J.; Wienkers, L. C.; Wynalda, M. A. J.
Med. Chem. 2003, 46, 284.
(5) Mosher, M. D.; Emmerich, L. G.; Frost, K. S.; Anderson, B. J.
Heterocycl. Chem. 2006, 43, 535.
́
(6) Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; Lopez-Vallejo, F.;
Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J. L.; Sbardella, G.
J. Med. Chem. 2011, 54, 7663.
(7) (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer,
A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43,
775. (b) Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.;
Graneto, M. J.; Kellogg, M. S.; Koboldt, C. M.; Yuan, J.; Zhang, Y. Y.;
Seibert, K. J. Med. Chem. 2000, 43, 1661.
(8) (a) Sidell, S.; Bulger, R. J.; Brodie, J. L.; Kirby, W. M. Clin.
Pharmacol. Ther. 1964, 5, 26. (b) Turck, M.; Ronald, A.; Petersdorf, R.
G. JAMA 1965, 192, 961. (c) Shaw, R. F.; Riley, H. D., Jr.; Bracken, E.
C. Clin. Pharmacol. Ther. 1965, 6, 492. (d) Micetich, R. G.; Raap, R. J.
J. Med. Chem. 1968, 11, 159. (e) Severin, A.; Tabei, K.; Tenover, F.;
Chung, M.; Clarke, N.; Tomasz, A. J. Biol. Chem. 2004, 279, 3398.
(9) (a) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826. (b) Kong,
W.; Guo, Q.; Xu, Z.; Wang, G.; Jiang, X.; Wang, R. Org. Lett. 2015, 17,
3686.
(10) Ticozzi, C.; Zanarotti, A. Tetrahedron Lett. 1994, 35, 7421.
(11) For selected examples, see: (a) Bianchi, G.; De Micheli, C.;
Gandolfi, R. J. Chem. Soc., Perkin Trans. 1 1972, 1711. (b) Chatterjee,
N.; Pandit, P.; Halder, S.; Patra, A.; Maiti, D. K. J. Org. Chem. 2008, 73,
D
DOI: 10.1021/acs.orglett.6b03380
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