Synthesis of functionalized 2,3-dihydroisoxazoles by domino reactions in water and unexpected ring-opening reactions of 2,3-dihydroisoxazoles

Article abstract of DOI:10.1039/c1ob06318a

α,α-Dicyanoolefins react with hydroxylamine to afford 2,3-dihydroisoxazoles (2,3-dihydroisoxazoles can be easily isolated by filtration) in excellent yields under mild and environmentally benign conditions. A one-pot reaction in tandem with an unexpected ring-opening of 2,3-dihydroisoxazoles has been developed as well.

Full text of DOI:10.1039/c1ob06318a

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Synthesis of functionalized 2,3-dihydroisoxazoles by domino reactions in
water and unexpected ring-opening reactions of 2,3-dihydroisoxazoles†‡
Ping Li, Bo-Tao Teng, Fa-Gen Jin, Xin-Sheng Li, Wei-Dong Zhu and Jian-Wu Xie*
Received 3rd August 2011, Accepted 27th September 2011
DOI: 10.1039/c1ob06318a
a,a-Dicyanoolefins react with hydroxylamine to afford 2,3-
dihydroisoxazoles (2,3-dihydroisoxazoles can be easily iso-
lated by filtration) in excellent yields under mild and envi-
ronmentally benign conditions. A one-pot reaction in tandem
with an unexpected ring-opening of 2,3-dihydroisoxazoles has
been developed as well.
proceed in low yields.7e,7g,7h The success of these methods is
often limited as in many cases the reaction conditions remain
harsh.7b,7d,7g,7h Toxic transition-metal catalysts and organic solvents
can cause significant air pollution, land contamination and water
pollution.7,8 Thus it remains highly desirable to develop a new
synthetic method that can be carried out under milder conditions
without using toxic transition-metal catalysts. Furthermore, the
development of an efficient synthetic methodology for organic
reactions, in the absence of organic solvents, is an important
challenge toward reducing the amount of waste. An ideal organic
reaction would proceed in an environmentally benign solvent,
such as water. To address this important issue, here we would
like to present a base-catalyzed domino reaction of electron-
deficient a,a-dicyanoolefins with hydroxylamines, providing a
facile, mild, efficient and environmentally benign approach to
trisubstituted 2,3-dihydroisoxazoles. For the first time, we report
the highly chemoselective unexpected ring-opening reactions of
2,3-dihydroisoxazoles to afford 2-cyano-a,b-unsaturated amides
under mild conditions.
Recently, our group9 and others10 have demonstrated that
electron-deficient a,a-dicyanoolefins are readily available and
attractive precursors for the construction of various acyclic
and cyclic compounds. Inspired by the recent reports,9–10 we
envisaged that 2,3-dihydroisoxazoles with multiple substitutions
might be prepared from the corresponding electron-deficient a,a-
dicyanoolefins and hydroxylamine by the new domino Michael
addition/intramolecular cyclization reactions.
In an initial study, we studied the reaction of NH2OH·HCl with
a,a-dicyanoolefin 1a, which can easily be prepared on a gram scale
in excellent yields according to the reported procedure.11 To our
delight, 2,3-dihydroisoxazole 2a was obtained in a yield of 78%
when the reaction was carried out at pH ~ 8 in water at room
temperature for 4 h (Table 1, entry 1). The yield was dramatically
increased when the pH value increased (Table 1, entries 2–3).
Interestingly, clean product 2a was obtained when the pH values
were in the region of 9–10. Surprisingly, both desired products 2,3-
dihydroisoxazole 2a and benzaldoxime 3a were isolated when the
pH value was increased (Table 1, entry 4). It was quite obvious that
the elimination of malononitrile took place under these conditions.
Only benzaldoxime 3a was obtained when the pH value was above
12 (Table 1, entry 5). Therefore, the reaction condition (pH = 9–10)
was chosen as our general strategy for the following work.
With the optimized conditions in hand, we then explored the
scope of the domino reactions by employing various substituted
2,3-Dihydroisoxazoles are an important class of heterocycles,
widely present in a number of bioactive molecules.1 In addition to
serving as drug and agrochemical targets, 2,3-dihydroisoxazoles
are also valuable as synthetic building blocks in organic synthesis
since the N–O bond can be easily cleaved under mild reducing
conditions.2 For example, highly substituted 2,3-dihydroisoxazoles
are particularly used as interesting starting materials in the
synthesis of 1,3-amino alcohols3–4 or 1,3-amino ketones3–5 More-
over, the rearrangement reactions of 2,3-dihydroisoxazoles are
well-known.6 It is therefore unsurprising that the development
of a new and efficient methodology for the synthesis of these
materials continuously commands considerable attention. The
most frequent synthetic methods used for the construction of
2,3-dihydroisoxazoles are of 1,3-dipolar cycloaddition reactions
between nitrones and alkynes or metal acetylides over transition
metals or Lewis acids as catalysts in the past years.7 Recently,
an Et3N-catalyzed tandem reaction of electron-deficient 1,3-
conjugated enynes with hydroxylamines for the construction of
2,3-dihydroisoxazoles has been developed by Zhang’s group.8
Although these methods have been used for years, there are
significant drawbacks: transition-metal-catalyzed 1,3-dipolar cy-
cloadditions often furnish regioisomeric mixtures of adducts and
Key Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Department of Chemistry and Life Science, Zhejiang Normal
University, 321004 Jinhua, China. E-mail: xiejw@zjnu.cn; Fax: +86-579-
82282610
† Electronic supplementary information (ESI) available: Copies of NMR
spectra as well as complete data for the reported crystal structure. CCDC
reference number 838125. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06318a
‡ Crystal data for 4a C10H8N2O (172.18), monoclinic, space group P21/n,
3
˚
˚
˚
˚
a = 10.3225(7) A, b = 11.2447(8) A, c = 16.7681(11) A, U = 1776.5(2) A ,
Z = 8, specimen 0.492 ¥ 0.453 ¥ 0.259 mm3, T = 296(2)K, SIEMENS
P4 diffractometer, absorption coefficient 0.086 mm-1, reflections collected
26305, independent reflections 4096 [R(int) = 0.0497], refinement by
full-matrix least-squares on F2, data/restraints/parameters 4096/0/235,
goodness-of-fit on F2 = 1.010, final R indices [I > 2s(I)] R1 = 0.0483, wR2 =
0.1209, R indices (all data) R1 = 0.1016, wR2 = 0.1477, largest diff. peak
-3
˚
and hole 0.129 and -0.175 e A .
244 | Org. Biomol. Chem., 2012, 10, 244–247
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Table 1 Reaction of a,a-dicyanoolefin 1a and NH2OH·HCl under
different conditionsa
Entry
pHb
Yield (%) 2ac
Yield (%) 3ac
1
2
3
4
5
8
9
10
11
12
78
91
90
16
0
0
0
68
75
trace
a Unless otherwise noted, reaction performed with 1 mmol of 1a, 10 mmol
of NH2OH·HCl, in 5 mL water at room temperature for 4 h. b Testing with
pH paper. c Isolated yield.
electron-deficient a,a-dicyanoolefins 1a–h. The results are shown
in Scheme 1. It is worthy of note here that a pale yellow
precipitate was formed when the reactions were carried out
at room temperature for 4 h and 2,3-dihydroisoxazoles were
easily isolated by filtration, then washed with water to give
the pure 2,3-dihydroisoxazoles in excellent yields. The domino
reaction was also proven effective and convenient to prepare 2,3-
dihydroisoxazoles on a large scale (>10 g, see Supplementary
Information†). The reaction scope was quite broad with respect to
a,a-dicyanoolefins 1. Various substituted electron-deficient a,a-
dicyanoolefins 1a–h with different substitutions were investigated.
The electronic effect was very marginal and remarkable yields were
achieved (Scheme 1, 2a–h) and a,a-dicyanoolefins with electron-
withdrawing substituents on the ortho, meta or para positions
afford 2,3-dihydroisoxazoles without affecting the yield (Scheme 1,
2d, 2g–h).
Scheme 2 Synthesis of multifunctionalized 2,3-dihydroisoxazoles (2i–2q)
and spiro-2,3-dihydroisoxazoles (2r–s).
possess electron-withdrawing groups in the phenyl ring (1l–n, 1q).
An electron-donating substituent on aryl ring of a,a-dicyanoolefin
substrates has a little effect on the yields (1j–k, 1p). Interestingly,
under the same conditions as aforementioned, for aliphatic cyclic
substrates 1r–s, the domino reactions proceeded very well to afford
spiro-2,3-dihydroisoxazoles (2r–s).
Having succeeded in synthesizing 2,3-dihydroisoxazoles and
spiro-2,3-dihydroisoxazoles possessing multiple substitutions
from various substituted electron-deficient a,a-dicyanoolefins and
NH2OH·HCl under mild conditions, we turned our attention
to the possible synthesis of functional compounds by this new
methodology. To our surprise, unexpected ring-opening product
2-cyano-3-phenyl-acrylamide 4a was isolated in quantitative yield
when 2,3-dihydroisoxazole 2a was stirred in diluted hydrochloric
acid (Scheme 3, (1)). From a synthetic point of view, one-pot
procedures beginning with simple, readily available substrates
provide ideal strategies in organic synthesis. It was envisioned
that some reactions would be processed in one pot between a,a-
dicyanoolefins and NH2OH·HCl. Therefore, we first investigated
the reaction of a,a-dicyanoolefin 1a with NH2OH·HCl under
the same conditions as described above. After stirring at room
temperature for 4 h, 2,3-dihydroisoxazole 2a was not separated.
Afterwards, hydrochloric acid (2 N HCl) was added until the
reaction pH was in the range of 1–3. After stirring at room
temperature for another 30 min, unexpected ring-opening product
Scheme 1 Synthesis of multifunctionalized 2,3-dihydroisoxazoles (2a–h).
Other bulkier a,a-dicyanoolefins 1i–q were also well tolerated
to give good yields while a longer reaction time was required
(Scheme 2). Although a sluggish reaction was observed even
at room temperature due to the very low solubility of a,a-
dicyanoolefins 1i–q in water, gratifyingly, the domino reactions
proceeded very well when THF and water were used in a 1 : 1 ratio
under the same conditions, and moderate to good yields (67%–
85%) were achieved after 14 h. Good yields were obtained in the
domino reactions of NH2OH·HCl with a,a-dicyanoolefins which
Scheme 3 Synthesis of 2-cyano-3-phenyl-acrylamide via one-pot tandem
reaction.
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2-cyano-3-phenyl-acrylamide 4a was isolated in a yield of 91%
(Scheme 3, (2)). The structure and stereochemistry of 4a were
established by X-ray analysis.12 It is obvious that highly chemos-
elective ring-opening reactions of 2,3-dihydroisoxazole 2a to
afford 2-cyano-3-phenyl-acrylamide 4a took place under these
conditions.
After the unexpected reactions of a,a-dicyanoolefins were in-
vestigated, more experiments were conducted to test the substrate
scope of the one-pot process and to gain further insight with
regard to the possible reaction mechanism. As shown in Scheme 4,
a variety of a,a-dicyanoolefins with different structures were
investigated. The electronic effect was also very marginal and
excellent yields were achieved for substrates 1. a,a-Dicyanoolefins
with electron withdrawing substituents on the ortho, meta or para
positions afford 2-cyano-3-aryl-acrylamides without affecting the
yields (Scheme 4, 4d, 4g–h).
On the basis of the experimental observations, a possible
mechanism was proposed to explain the one-pot tandem reactions.
As shown in Scheme 6, the Michael reaction between the highly
reactive a,a-dicyanoolefins 1 and hydroxylamine proceeded very
well to afford the intermediates I under the basic conditions. 2,3-
Dihydroisoxazoles 2 were readily obtained via an intramolecular
addition of the OH group on the cyano moiety and proton transfer.
Then 2,3-dihydroisoxazoles 2 were protonated, followed by a single
electron-transfer (SET) mechanism14 to afford open-ring products
4 (Path A). Open-ring products 4 were also obtained by addition
of H2O to intermediates II, then hydroxylamine was eliminated as
a leaving group (Path B). Path A is more preferred than Path B by
the DFT calculations.15a
Scheme 4 Reaction scope of a,a-dicyanoolefins 1 in the one-pot tandem
reaction.
Interestingly, under the same conditions as described above, for
other bulkier a,a-dicyanoolefins (Scheme 5, 1j, 1o), 2-cyano-3-
aryl-but-2-enoic acid derivatives 5j and 5o were isolated in good
yields, respectively (Scheme 5, eq. 1). Apparently the unexpected
ring-opening reactions took place, and a further hydrolysis of the
amide group occurred to generate the observed acid products.
Since the direct Knoevenagel reactions of unmodified ketones,
especially for aryl ones, with 2-cyanoacetic acid, have been rarely
reported to date,13 the readily available and easily handled a,a-
dicyanoolefins could act as versatile and highly reactive precursors
of ketones in such reactions. In addition, for aliphatic cyclic
substrate 1s, hydrolyzed product 5s was isolated in good yield
(Scheme 5, eq. 2).
Scheme 6 Plausible mechanism for the one-pot tandem reaction.
In summary, we have developed an extremely facile and
mild synthesis of trisubstituted 2,3-dihydroisoxazoles, including
spirocyclic compounds that are potentially relevant to natural
product synthesis, by the reaction of hydroxylamine with a,a-
dicyanoolefins 1 as well as developed a one-pot reaction in
tandem with an unexpected ring-opening of 2,3-dihydroisoxazoles
to afford 2-cyano-3-aryl-acrylamides and 2-cyanobut-2-enoic
acid derivatives. Both reactions employ very simple and readily
available substrates and tolerate a range of functional groups
to produce substituted 2,3-dihydroisoxazoles, 2-cyano-3-aryl-
acrylamides and 2-cyanobut-2-enoic acid derivatives with mod-
erate to excellent yields. Additionally, the reactions can be carried
out in water as a cheap and environmentally benign solvent, and a
simple purification step provides the products in good yields. The
method for the synthesis of trisubstituted 2,3-dihydroisoxazoles
can be conducted on a larger scale (>10 g)15b at low cost
making it an ideal alternative to existing methods. Two plausible
mechanisms for this unprecedented ring-opening reaction were
given. We anticipate that this work would arouse more interest
in the chemistry of 2,3-dihydroisoxazoles. Further development
of this reaction including studies on the reaction mechanism and
scopes, is being pursued and will be reported in due course.
Scheme 5 One-pot tandem reaction of other bulkier a,a-dicyanoolefins
1 and NH2OH·HCl.
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Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (20902083), the Natural Science
Foundation of Zhejiang Province, China (Y4090082, R4080084),
and the Program for Changjiang Scholars and Innovative Re-
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