Reductive ring cleavage of nonconjugated Δ2-isoxazolines to β-hydroxy ketones with aluminum and copper(II) chloride

Article abstract of DOI:10.1055/s-0031-1290310

A facile, economic, and efficient protocol for the reduction of nonconjugated Δ²-isoxazolines to the corresponding β-hydroxy ketones using Al/CuCl₂ as the reducing agent has been developed. The method is both rapid and complete requiring less than ten minutes to attain total ring cleavage. This is the first example of using an in situ prepared Al/Cu couple in organic synthesis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290310

LETTER
381
Reductive Ring Cleavage of Nonconjugated D2-Isoxazolines to b-Hydroxy
Ketones with Aluminum and Copper(II) Chloride
R
eductio
e
n
of
D
-
2Isoxvazolines to
a
b
-Hydroxy Keton
K
es by Al/Cu
C
oupl
a
e
rpaviciene, Ringaile Lapinskaite, Algirdas Brukstus, Inga Cikotiene*
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: inga.cikotiene@chf.vu.lt
Received 6 October 2011
dipolar cycloaddition method.1 Having in hand the requi-
site substrates, we could test their reactivity towards dif-
ferent reduction conditions. The results are shown in
Table 1. First of all, we choose isoxazolines 1a and 1b as
Abstract: A facile, economic, and efficient protocol for the reduc-
tion of nonconjugated D2-isoxazolines to the corresponding b-hy-
droxy ketones using Al/CuCl2 as the reducing agent has been
developed. The method is both rapid and complete requiring less
than ten minutes to attain total ring cleavage. This is the first exam- model substrates and tried the recently discovered low-
ple of using an in situ prepared Al/Cu couple in organic synthesis.
cost reduction method by the Fe/NH4Cl system (Table 1,
entries 1 and 2).9 The starting materials were consumed
completely within four hours; but yields of the desired b-
hydroxy ketones 2a,b were moderately low. Moreover, in
the case of starting material 1b, we observed the forma-
Key words: reduction, isoxazolines, b-hydroxyketones, aluminum/
copper couple
D2-Isoxazolines constitute of a class of heterocycles that
tion of two side products – 1-phenyl-2-hepten-1-one,
formed after the elimination of water and methyl phenyl
ketone, formed after the retro-aldol reaction. After these
unsatisfactory results, we turned our attention to the pos-
sible use of bimetallic systems.
are most commonly assembled by a dipolar cycloaddition
reaction of a nitrile oxide and an alkene.1 Besides being
potential pharmaceutical agents,2 isoxazolines have found
numerous applications in synthesis through reductive
cleavage of the N–O bond to give 1,3-amino alcohols or
b-hydroxy ketones through hydroxyimine intermediates.3
b-Hydroxy ketones have attracted the scientific interest as
useful building blocks in organic synthesis4 and, more-
over, as biologically significant scaffolds.5 Reduction of
isoxazolines can be accomplished using Raney-Ni,6
Mo(CO)6,7 SmI2,8 Fe/NH4Cl,9 TiCl3,6b,10 EtMgBr/Ti(Oi-
Pr)4,11 and some other reagents.12
Bimetallic reductive systems such as Fe/Pd, Fe/Cu, Fe/
Co, Zn/Cu, Pd/Ag, Pd/Cu, Pt/Cu, Al/Cu, etc. are known as
effective catalysts mainly for dechlorination of various
chlorinated hydrocarbons, and they were studied particu-
larly for potent groundwater remediation.14 We chose an
in situ preparation of several inexpensive couples such as
Fe/Cu, Zn/Cu, and Al/Cu and tested their reactivity to-
wards the reductive cleavage of the isoxazolines.
The reductive systems Al/Cu, Zn/Cu and Fe/Cu were pre-
pared in situ by adding an aqueous solution of copper(II)
salts to mixtures of starting isoxazolines and the corre-
sponding metal in methanol. No reaction was observed by
TLC when we tried to use aluminum cuttings and cop-
per(II) sulfate (Table 1, entry 3). Addition of sodium chlo-
ride to the reaction mixture solved this problem probably
by destroying of the aluminum oxide layer. So the com-
plete consumption of starting material was reached in five
minutes (Table 1, entry 4). Using copper(II) chloride in-
stead of the combination CuSO4/NaCl slightly increased
the yield of the product (Table 1, entries 5, 6) and, logical-
ly, the use of aluminum dust gave a better result in com-
parison to aluminum cuttings. However, using the Zn/Cu
system was not so effective – the conversion of 1a was
only 25% (Table 1, entry 7) and, moreover, the couple Fe/
Cu was inactive at all (Table 1, entry 8). It should be noted
that 5-butyl-3-phenyl-4,5-dihydroisoxazole (1b) was re-
covered unchanged after the treatment with Al/CuCl2 or
Zn/CuCl2 systems (Table 1, entries 9, 10). So it is possible
to conclude that the Al (dust)/CuCl2 system in methanol–
aqueous media is the best reaction condition for the reduc-
tive cleavage of nonconjugated isoxazolines.
O
OH
R2
N
O
R2
R1
R1
Scheme 1 Reductive ring cleavage of D2-isoxazolines
Although a lot of synthetic methods for the preparation of
b-hydroxy ketones from D2-isoxazolines are already
known, development of fast, economic, and ecological
ways are formidable tasks for organic chemists
(Scheme 1). Moreover, there is a growing interest in car-
rying out important synthetic transformations in aqueous
media.13 We report herein a simple and mild procedure for
the reduction of D2-isoxazolines using aluminum powder
and copper(II) chloride in aqueous methanol, where ex-
cellent discrimination between conjugated and nonconju-
gated isoxazolines has been observed.
During our investigations aimed on the synthesis of bio-
logically important b-hydroxy ketones, we have synthe-
sized various isoxazolines 1a–p using a well-known
SYNLETT 2012, 23, 381–384
x
x.
x
x.
2
0
1
1
Advanced online publication: 19.01.2012
DOI: 10.1055/s-0031-1290310; Art ID: D52311ST
© Georg Thieme Verlag Stuttgart · New York

382
I. Karpavičiene
LETTER
Table 1 Reaction Conditions for the Reductive Cleavage of 3-Substituted 5-Butyl-4,5-dihydroisoxazoles 1a,b
O
OH
N
O
Bu
R
R
Bu
2a,b
1a,b
1a, 2a: R = Hex
1b, 2b: R = Ph
Entry
Starting material
Reaction conditions
Conv. (%)
Yield of 2 (%)
1
2
1a
1b
1a
1a
1a
1a
1a
1a
1b
1b
Fe/NH4Cl, EtOH–H2O, 80 °C
100
100
0
50
36
–
Fe/NH4Cl, EtOH–H2O, 80 °C
3
Al (cuttings), CuSO4·5H2O, MeOH–H2O, r.t.
Al (cuttings), CuSO4·5H2O, NaCl, MeOH–H2O, r.t.
Al (cuttings), CuCl2·2H2O, MeOH–H2O, r.t.
Al (dust), CuCl2·2H2O, MeOH–H2O, r.t.
Zn (dust), CuCl2·2H2O, MeOH–H2O, r.t.
Fe, CuCl2·2H2O, MeOH-H2O, r.t.
4
100
100
100
25a
0
73
76
82
18b
–
5
6
7
8
9
Al (dust), CuCl2·2H2O, MeOH–H2O, r.t.
Zn (dust), CuCl2·2H2O, MeOH–H2O, r.t.
5a
–
10
0
–
a Conversions determined from NMR of crude mixtures.
b Yield of pure product.
Encouraged by these results we decided to perform the observed earlier, the starting materials bearing aryl moiety
synthesis of various b-hydroxy ketones according to the in the 3-position of the isoxazoline ring were unreactive
presented method. The results are summarized in Table 2. towards the reaction conditions (Table 2, entries 2, 12,
All nonconjugated starting izoxazolines underwent and 13). The effect of conjugation is clearly seen from the
smooth reductive ring cleavage (Table 2, entries 1, 3–9). comparison of the reduction of two isomeric compounds
When 5-hydroxymethyl D2-isoxazoline 1g was subjected – 5-butyl-3-phenyl-4,5-dihydroisoxazole (1b, Table 2,
to the reductive conditions, the reaction occurred smooth- entry 2) and 3-butyl-5-phenyl-4,5-dihydroisoxazole (1d,
ly and cleanly, as observed by TLC (Table 2, entry 7). Table 2, entry 4). In the case of 5-cyclohexyl-3-(4-nitro-
However, the corresponding product 2g was not stable, phenyl)-4,5-dihydroisoxazole (1p), complete reduction of
and about 15% of it underwent hydroxy elimination and the nitro group was observed while the heterocyclic ring
subsequent condensation to form 2-hexylfuran during the remained unchanged (Table 2, entry 14). Therefore, we
workup and purification procedure. In the case of 5-tert- tried to reduce the nitro groups in simple aromatic com-
butyl-3-(1-propenyl)-4,5-dihydroisoxazole (1l), the re- pounds 3a,b and obtained the corresponding anilines 4a,b
duction of the C=C bond was also observed (Table 2, en- in satisfactory yields (Table 2, entries 15, 16).
try 10). But, on the other hand, 5-tert-butyl-3-(2-
phenylethenyl)-4,5-dihydroisoxazole (1m) remained un-
affected during the reaction (Table 2, entry 11). As it was
Table 2 Data on the Synthesis of b-Hydroxy Ketones by the Presented Method15
Entry
Starting material
Product
Yield (%)
84
O
OH
O
N
1
Bu
Hex
Hex
2a
O
Bu
1a
OH
O
N
2
3
14a
76
Bu
Ph
Ph
2b
O
Bu
1b
OH
O
N
OAc
OAc
Bu
Bu
1c
2c
Synlett 2012, 23, 381–384
© Thieme Stuttgart · New York

LETTER
Reduction of D2-Isoxazolines to b-Hydroxy Ketones by Al/Cu Couple
383
Table 2 Data on the Synthesis of b-Hydroxy Ketones by the Presented Method15 (continued)
Entry
4
Starting material
Product
Yield (%)
72
O
OH
OH
O
N
Ph
Bu
Bu
Bu
2d
O
Ph
Bu
1d
O
N
5
6
7
52
Bu
Bu
2e
O
1e
OH
O
N
74b
82c
t-Bu
Hex
Hex
2f
t-Bu
1f
O
OH
OH
O
O
N
N
OH
OH
Hex
Hex
2g
O
1g
Hex
Hex
8
76
1h
2h
O
OH
O
N
9
10
11
89
71
–
c-Hex
t-Bu
c-Hex
c-Hex
c-Hex
1k
2k
O
OH
O
N
t-Bu
1l
2l
O
N
no reaction
Ph
t-Bu
1m
O
OH
O
N
Bu
Bu
12
13
14
tracea
F
F
1n
2n
O
O
N
Bu
no reaction
–
MeO
1o
O
N
N
80
O2N
H2N
1p
1r
NH2
NO2
15
16
79
75
4a
3a
MeO
NH2
NO2
MeO
MeO
MeO
3b
4b
a Incomplete conversion of the starting material.
b The product was unstable, and 20% of it converted into 2,2-dimethyl-3-undec-5-ene.
c The product was unstable, and 15% of it converted into 2-hexylfurane during workup.
© Thieme Stuttgart · New York
Synlett 2012, 23, 381–384

384
I. Karpavičiene
LETTER
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In summary, the reduction using Al/CuCl2 provides a fac-
ile, economical, and efficient protocol for the preparation
of b-hydroxy ketones. The procedure is particularly useful
for the transformation of nonconjugated D2-isoxazolines
to b-hydroxy ketones, as well as for reduction of aromatic
nitro compounds. Moreover, this is the first example of
using an in situ prepared aluminum/copper couple in or-
ganic synthesis. Advantages of the presented method in-
clude low cost, neutral media, and short reaction times (up
to 10 min). This method should be of considerable interest
for the construction of synthetically useful and complex
biologically active molecules. The investigation of using
the Al/Cu couple in organic synthesis is carrying out in
our laboratory, and the results will be published in due
course.
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Disubstituted 4,5-Dihydroisoxazoles 1
Acknowledgment
The research was funded by the European Social Fund under the
Global Grant measure (Grant No. VP1-3.1-MM-07-K-01-002).
References and Notes
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To the mixture of the corresponding 3,5-disubstituted 4,5-
dihydroisoxazole (1, 1 mmol) and Al dust (0.81 g, 30 mmol)
in MeOH (5 mL) a solution of CuCl2×2H2O (1.75 g, 10
mmol) in H2O (5 mL) was added dropwise under vigorous
stirring. After the evolution of hydrogen and full
consumption of the starting material (observed by TLC,
approximately after 5–10 min), the mixture was diluted with
H2O (30 mL), and the product was extracted with CHCl3 (2
×30 mL). The organic layer was dried over Na2SO4,
evaporated under the reduced pressure, and the residue
purified by column chromatography to give 2.
Analytical Data for 5-Hydroxy-7-tridecanone (2a)
Yield: 84%; colorless oil. IR (KBr): nmax = 3410 (OH), 1706
(C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 0.88 (3 H, t,
J = 7.5 Hz, CH3), 0.91 (3 H, t, J = 7.5 Hz, CH3), 1.28–1.60
(14 H, m, 7 CH2), 2.43 [2 H, t, J = 7.5 Hz, C(8)H2], 2.48–
2.54 [1 H, m, C(6)H], 2.57–2.64 [1 H, m, C(6)H], 3.03 (1 H,
br s, OH), 3.99–4.07 [1 H, m, C(5)H] ppm. 13C NMR (75 Hz,
CDCl3): d = 13.8 (CH3), 13.9 (CH3), 22.4, 22.6, 23.5, 27.6,
28.7, 31.5, 36.1 (C-4), 43.6 (C-8), 48.9 (C-6), 67.5 (C-5),
212.6 (C-7) ppm. Anal. Calcd for C13H26O2: C, 72.84; H,
12.23. Found: C, 73.00; H, 12.19.
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Compounds 1–4 were also fully characterized by IR, 1H
NMR, 13C NMR spectroscopic and microanalytical data, and
data for known compounds are in agreement with published
data.
(6) (a) Romanski, J.; Nowak, P.; Jurczak, J.; Chapuis, C.
Tetrahedron: Asymmetry 2011, 22, 787. (b) Curran, D. P.;
Synlett 2012, 23, 381–384
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