Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles

Article abstract of DOI:10.1002/anie.201511730

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.

Full text of DOI:10.1002/anie.201511730

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Communications
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International Edition: DOI: 10.1002/anie.201511730
German Edition: DOI: 10.1002/ange.201511730
Heterocycles
Water-Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles
and Stereoselective Syntheses of Isoxazolines and 1,2,4-Oxadiazoles
Chatchai Kesornpun, Thammarat Aree, Chulabhorn Mahidol, Somsak Ruchirawat, and
Prasat Kittakoop*
Abstract: Conventional methods generate nitrile oxides from
oxime halides in organic solvents under basic conditions.
However, the present work revealed that water-assisted gen-
eration of nitrile oxides proceeds under mild acidic conditions
(pH 4–5). Cycloadditions of nitrile oxides with alkynes and
alkenes easily occurred in water without using catalysts, thus
Figure 1. Synthesis of isoxazolines and isoxazoles.
yielding isoxazoles and isoxazolines, respectively, with excel-
lent stereoselectivity toward five- and six-membered cyclic
alkenes. A double stereoselective cycloaddition of two units of
a nitrile oxide with cyclohexene was also achieved, thus
yielding 1,2,4-oxadiazole derivatives having a unique hybrid
isoxazoline-oxadiazole skeleton. Enantiomerically pure iso-
xazolines were prepared from monoterpenes with a ring strain.
In one case, the isoxazoline with a butterfly-like structure was
simply prepared, and it might be used as a ligand in asymmetric
catalysis.
and 1,3-dicarbonyl compounds,[7] copper nitrate trihydrate as
a source of nitrile oxides,[8] copper-catalyzed oxyazidation of
unactivated alkenes,[9] and an asymmetric hydroxylamine/
enone cascade reaction.[10] Cycloaddition of a nitrile oxide
and alkyne is also widely used in click chemistry, particularly
for nucleic acids and materials chemistry,[11] and such a cyclo-
addition is strictly performed either under basic conditions or
using metal catalysts. Organic reactions in water can not only
be considered green chemistry (abundance in nature and
environmentally friendly solvent), but also have the advant-
age of being run in biological systems (e.g., click reactions,
bioconjugation, and bioorthogonal chemistry). As part of our
research program directed at green chemistry approaches for
the synthesis of bioactive molecules,[12] we report herein the
synthesis of isoxazolines, 1,2,4-oxadiazoles, and isoxazoles in
aqueous solutions. Since the reactions in water have both
environmental and economic advantages, efforts to generate
the nitrile oxide in water have been made for the synthesis of
isoxazolines and isoxazoles.[13] Herein we show that nitrile
oxides can be generated from oxime halides in catalyst-free
aqueous solutions, and that the cycloaddition of nitrile oxide
with alkenes and alkynes occurs under acidic conditions,
rather than under the conventional basic conditions
(Figure 1).
We first examined the catalyst-free synthesis of isoxazo-
line using the coupling of 1a and 2a (Figure 2) as a model
reaction, thus giving the isoxazoline 3aa and the dimer 1aa as
products.[14] We found that alkenes with an amine group gave
trace amounts of isoxazoline,[14] thus suggesting that the pH of
the reaction mixture has significant influence on the yield.
Further experiments revealed that the generation of nitrile
oxide is assisted by water, and that the cycloaddition reaction
is pH dependent.[14] The presence of water was found to be
essential for the reaction.[14] Investigation of the pH effects on
the formation of 3aa in a phosphate buffer revealed that the
optimum reaction conditions were at pH 4–5.[14] Note that
yields (51–60%) for the reactions at neutral conditions
(pH 6–7) were relatively high, thus suggesting that this
method is applicable to research dealing with biomolecules,
for example, bioconjugation and bioorthogonal chemistry.
T
he chemistry of nitrile oxides is well established, partic-
ularly for the synthesis of isoxazoles, isoxazolines, and
oxadiazoles.[1] Isoxazoline scaffolds are found in many
biologically active compounds,[2] while isoxazoles exhibit
various biological activities,[3] and its scaffold is found in
many drugs, for example, flucloxacillin, valdecoxib, and
dicloxacillin. 1,2,4-Oxadiazoles are important scaffolds in
advanced materials and bioactive compounds.[4] Normally,
isoxazolines and isoxazoles are synthesized by a cycloaddition
of nitrile oxides with alkenes and alkynes. It has long been
known that the generation of nitrile oxides from oxime
halides occurs under basic conditions (Figure 1). Therefore,
the synthesis of isoxazolines and isoxazoles is carried out in
solvents containing bases as catalysts.[1,5] However, isoxazo-
lines and isoxazoles can also be prepared by other methods,
for example, using transition-metal catalysts (ruthenium or
palladium),[6] silver-mediated radical cyclization of ketoximes
[*] C. Kesornpun, Prof. Dr. C. Mahidol, Prof. Dr. S. Ruchirawat,
Dr. P. Kittakoop
Chulabhorn Graduate Institute, Chemical Biology Program
Kamphaeng Phet 6 Road, Laksi, Bangkok 10210 (Thailand)
E-mail: prasat@cri.or.th
Dr. T. Aree
Department of Chemistry, Faculty of Science
Chulalongkorn University, Bangkok 10330 (Thailand)
Prof. Dr. C. Mahidol, Prof. Dr. S. Ruchirawat, Dr. P. Kittakoop
Chulabhorn Research Institute, Bangkok 10210 (Thailand)
Prof. Dr. S. Ruchirawat, Dr. P. Kittakoop
Center of Excellence on Environmental Health and Toxicology (EHT),
CHE, Ministry of Education (Thailand)
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201511730.
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3bb–db), while those with 1e and 1 f led to lower yields of
33% (3eb) and 63% (3 fb), respectively. These results
implied that the EWGs enhanced the isoxazoline formation.
Both the oxime chlorides 1g and 1h have a C2 ketone, but the
yield of 3gb (62%) was more than that of 3hb (24%) because
1g has an EWG (aromatic ring). The oxime chloride 1i also
has an EWG (pyridin-2-yl), thus giving a relatively high yield
(66%) of 3ib. The oxime chloride 1j gave the isoxazoline 3jb
with 26% yield, but its corresponding saturated derivative 1k
did not give 3kb, thus supporting the fact that an EWG at C2
of the oxime chlorides is critically important for the reaction.
As expected, oxime derivatives (1l–o), lacking an EWG at C2
did not give the products 3lb–ob. Note that only isoxazolines
having a cis configuration were obtained from 2b, as revealed
by X-ray analysis of 3bb and 3ib.[15]
Next we investigated the reactivity of oxime chlorides
toward terminal and internal alkenes. Terminal alkenes (2c–f;
Figure 2) reacted with oxime chlorides (1a or 1b or 1i), thus
giving the isoxazolines 3ac, 3bc, 3id, and 3ie. with respective
yields of 71, 51, 60, and 92% (see Figure 2S in the Supporting
Information).[16] The diene 2 f reacted with 1i, thus giving
isoxazoline 3if (54%) and bisoxazoline 3iif (12%; Scheme 2).
Figure 2. Oxime chlorides (1a–o) and dipolarophiles (2a–o and 7a–i)
used in this study. Dipolarophiles: (2b; red) gave products in
Scheme 1; (2c–j; blue) gave products in Schemes 2 and 3; (2k–o;
pink) gave products in Scheme 4; (7a–i; green) gave products in
Scheme 5.
Next, the scope for oxime chloride substrates was inves-
tigated by exploring the reactions of indene (2b) with
different oxime chlorides (1b–o) (Figure 2) in a phosphate
buffer at pH 4.0 (Scheme 1). Note that acetone was added to
the reaction because it increased the substrate solubility.
Effects of electron-withdrawing groups (EWG) and electron-
donating groups (EDG) were studied using aromatic oxime
chlorides substituted with either EWGs (NO2, Cl, and Br (1b–
d)) or an EDG (1e), or without any substitution (1 f). The
oxime chlorides 1b–d gave high product yields (76–81%;
Scheme 2. Synthesis of isoxazolines. Reaction conditions: oxime chlo-
ride (1.2 equiv), alkenes (1.0 equiv), acetone (0.5 mL), 0.1m phosphate
buffer (10.0 mL), pH 4.0, RT, 15 h. However, the mole ratio of oxime
chloride/alkene for the synthesis of 3bi and 3di was 1.0:4.0.
These isoxazolines have quaternary carbon center. The
internal alkenes 2g and 2h reacted with 1a, thus yielding
3ag (53%) and 3ah (33%), respectively. Normally, isoxazo-
lines with a JH-4,H-5 value of about 8 Hz are trans isomers, while
those with a J value of about 12 Hz are cis forms.[17] The JH-4,H-5
value of about 8 Hz for both 3ag and 3ah indicate that they
are trans isomers, thus suggesting that the reaction with
internal alkenes selectively gives trans isoxazolines. The
isoxazolines 3bi–di and 3 fi were obtained from cyclopentene
(2i) in good yields, and they were cis isomers as revealed by
X-ray analysis of 3bi.[15]
Interestingly, the reaction of cyclohexene (2j) and 1b–d,
using a mole ratio of 1.2:1.0 for the oxime chloride and
alkene, gave the 1,2,4-oxadiazole derivatives 4bbj, 4ccj, and
4ddj (Scheme 3). The products have a unique 6/5/5 ring
system, having a hybrid isoxazoline-oxadiazole skeleton
derived from a double cycloaddition with two units of the
nitrile oxide. However, the less reactive oxime chlorides (i.e.,
1a, 1i, and 1 f) gave only a single cycloaddition product, that
is, 3aj, 3ij, and 3 fj with yields of 30%, 14%, and 7%,
Scheme 1. Synthesis of isoxazolines. Reaction conditions: oxime chlo-
ride (1.2 equiv), 2b (1.0 equiv), acetone (0.5 mL), 0.1m phosphate
buffer (10.0 mL), pH 4.0, RT, 15 h.
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ring strain to that of norbornene, therefore we selected these
monoterpenes for the cycloaddition. These terpenes have an
sp2-hybridized quaternary carbon center, and we anticipated
that the newly generated quaternary carbon center in the
isoxazoline products would have the same stereoselectivity as
that in oxadiazoles (Scheme 3).
The enantiomerically pure monoterpene, (1R)-(+)-a-
pinene [(+)-2k], reacted with 1b to yield 48% of the
isoxazoline having a negative optical rotation, that is (À)-
6bk (Scheme 4). The reaction gave (À)-6bk as a single
Scheme 3. Synthesis of oxadiazoles. Reaction conditions for formation
of 4bbj, 4ccj, and 4ddj: oxime chloride/alkene=1.2:1.0 equiv, acetone
(0.5 mL), 0.1m phosphate buffer (10.0 mL), pH 4.0, RT, 15 h. Reaction
conditions for formation of 4bcj, 4cbj, 5dbi, and 5dci: oxime chloride/
isoxazoline=2.0:1.0 equiv, acetone (0.2 mL), phosphate buffer
(1.0 mL), pH 4.0, RT, 15 h. For ORTEP structures thermal ellipsoids
shown at 20% probability.
respectively (see Figure 3S in the Supporting Information).[16]
The X-ray analysis[15] of 4bbj revealed a cis-fused 6,5-
membered ring, and the isoxazoline unit was perpendicular
to the oxadiazole moiety (Scheme 3). Unexpectedly, quater-
nary carbon center in the 1,2,4-oxadiazole derivatives was
stereoselectively constructed under mild reaction conditions.
Increasing the mole ratio of the alkene, that is, using a 1:10
ratio for oxime chloride and alkene, gave products of a single
cycloaddition (3bj, 3cj, and 3dj with respective yields of
33%, 33%, and 40%, respectively).[16] Therefore, the alkene
mole ratio determines whether oxadiazoles or isoxazolines
are formed. We propose that isoxazolines (i.e., 3bj, 3cj, and
3dj) are first formed, and the cycloaddition of a second nitrile
oxide to these isoxazolines gives rise to the formation of the
corresponding 1,2,4-oxadiazoles. This reaction mechanism
prompted us to synthesize 1,2,4-oxadiazoles derived from two
different nitrile oxide units. Isoxazolines (i.e., 3bj, 3cj, 3dj,
and 3ij) were prepared with the first nitrile oxide unit, and
subsequent cycloaddition with the second nitrile oxide gave
the 1,2,4-oxadiazoles 4bcj, 4cbj, 4ibj, and 4idj, respectively
(Scheme 3 and Figure 3S).[16] Moreover, the method was used
for isoxazolines derived from 2i, thus giving oxadiazoles with
a unique 5/5/5 ring system, that is, 5dbi, 5dci, and 5idi
(Scheme 3 and Figure 3S).[16] Although several oxadiazoles
have been synthesized through nitrile oxide chemistry,[1,13e]
the preparation of the novel hybrid isoxazoline-oxadiazoles
presented here has never been reported. Moreover, the
stereoselective synthesis of these oxadiazoles was achieved
under mild conditions.
Scheme 4. Preparation of enantiomerically pure isoxazolines. Reaction
conditions: oxime chloride (1.2 equiv), alkene (1.0 equiv), acetone
(0.5 mL), 0.1m phosphate buffer (10.0 mL), pH 4.0, RT, 15 h. For
ORTEP structures thermal ellipsoids shown at 20% probability.
product, thus implying that only one enantiomer was obtained
from the reaction. In contrast, the enantiomer, (1S)-(À)-a-
pinene [(À)-2k], yielded the isoxazoline with a positive
optical rotation, (+)-6bk, in a yield of 48%. X-ray analysis[15]
confirmed the structures of (À)-6bk and (+)-6bk. The
reaction of (+)-2k with 1a and 1i gave (À)-6ak (48%
yield) and (À)-6ik (21% yield), respectively (see Figure 4S in
the Supporting Information).[16] Enantiomerically pure ter-
penes, (1R)-(À)-myrtenol [(À)-2l], (1R)-(À)-myrtenyl ace-
tate [(À)-2m], and (1S)-(À)-verbenone [(À)-2n] reacted with
1b, thus giving (+)-6bl (41%), (À)-6bm (51%), and (À)-6bn
(74%), respectively (see Figure 4S in the Supporting Infor-
mation).[16] Interestingly, (1R)-(À)-myrtenal [(À)-2o] gave
(À)-6bo (22% yield) and the bis(acetal) derivative (bis)6bo
(27% yield; Scheme 4). It was found that (À)-6bo was easily
converted into (bis)6bo during crystallization, and it has
a plane of symmetry (meso form), and its butterfly-like
structure was confirmed by X-ray analysis (Scheme 4).[15]
Such a unique structure is possibly useful as a ligand in
asymmetric catalysis.
Since the cycloaddition reaction in mild acidic aqueous
solution is stereoselective, we next aimed to utilize this
method for the synthesis of enantiomerically pure isoxazo-
lines. In addition to being important scaffolds in bioactive
molecules, isoxazolines are used as ligands in asymmetric
catalysis.[18] It is known that the cycloaddition of nitrile oxides
with norbornene and derivatives proceed with exo-stereose-
lectivity, however, two possible isomers (anti and syn) were
obtained from the reaction.[19] Monoterpenes, such as a-
pinene (2k) and (1R)-(À)-myrtenol [(À)-2l], have similar
Next we preliminarily investigated the catalyst-free cyclo-
addition for the synthesis of isoxazoles. The external alkynes
7a–f (Figure 2) reacted with either 1a or 1c, thus giving the
isoxazoles 8aa, 8cb, 8ac, 8cd, 8ce, and 8cf with yields of 44%,
67%, 32%, 77%, 40%, and 50%, respectively (Scheme 5 and
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Scheme 5. Synthesis of isoxazoles. Reaction conditions: oxime chloride
(1.2 equiv), alkyne (1.0 equiv), acetone (0.5 mL), 0.1m phosphate
buffer (10.0 mL), pH 4.0, RT, 15 h.
see Figure 5S in the Supporting Information).[16] Note that the
catalyst-free cycloaddition could be employed with either an
acid (7a) or alcohols (7c–e) without functional-group pro-
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the internal alkyne 7i gave the major isomers 8ai and 8bi
(each with 8% yield), together with a trace amount of the
minor isomer (observed from 1H NMR spectra of crude
reaction mixtures).
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nitrile oxides can be generated from oxime halides in aqueous
solution without using any catalysts. The formation proceeds
under mild acidic conditions, as opposed to basic conditions
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solution had excellent stereoselectivity, and it was used for the
synthesis of 1,2,4-oxadiazoles and enantiomerically pure
isoxazolines. The catalyst-free cycloaddition was also used
for the synthesis of isoxazoles. We propose that the formation
of nitrile oxide from oxime chloride in water is initiated by the
loss of a chlorine atom from the oxime chloride with
subsequent abstraction of the oxime proton by chloride ion.
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Acknowledgements
This work is supported by the Center of Excellence on
Environmental Health and Toxicology, Science & Technology
Postgraduate Education and Research Development Office
(PERDO), Ministry of Education. T. Aree thanks the
Ratchadapisek Sompoch Endowment Fund, Chulalongkorn
University (CU-58-021-FW) and the National Research
University Project of Thailand (WCU-58-013-FW) for finan-
cial support.
Keywords: alkenes · cycloaddition · green chemistry ·
heterocycles · water
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[14] Details of experiments and results are in the Supporting
Information.
[15] Details of the single-crystal X-ray analysis and ORTEP plots are
in Table 4S and Figure 1S (see the Supporting Information),
respectively. CCDC 1434333– 1434339 ((Bis)6bo, (+)-6bk, (À)-
6bk, 4bbj, 3bi, 3ib, and 3bb) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
[16] Structures and yields are in the Supporting Information.
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Received: December 18, 2015
Published online: February 23, 2016
Angew. Chem. Int. Ed. 2016, 55, 3997 –4001
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4001