Cu(0) nanoparticle catalyzed efficient reductive cleavage of isoxazoline, carbonyl azide and domino cyclization in water medium

Article abstract of DOI:10.1039/c2gc35252d

Small Cu(0)-nanoparticles (NPs) are fabricated utilizing CuSO ₄·5H₂O, surfactant (SDS) and ascorbic acid in aqueous medium. Its outstanding catalytic activity under low catalyst loading is developed toward reductive cleavage of isoxazoline, carbonyl azide and domino cyclization to furnish valuable 2-hydroxy-4-keto esters, primary amides and a new class of heterocycle, 4-hydroxy-2-pyrroline-5-one. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2gc35252d

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COMMUNICATION
Cu(0) nanoparticle catalyzed efficient reductive cleavage of isoxazoline,
carbonyl azide and domino cyclization in water medium†
Krishnanka S. Gayen,a Tista Sengupta,a Yasmin Saima,a Adita Das,a Dilip K. Maiti*a and Atanu Mitra*b
Received 20th February 2012, Accepted 30th March 2012
DOI: 10.1039/c2gc35252d
Cu(0)-NPs. In our experiment,
a
cooperative assembly3a
Small Cu(0)-nanoparticles (NPs) are fabricated utilizing
CuSO4·5H2O, surfactant (SDS) and ascorbic acid in aqueous
medium. Its outstanding catalytic activity under low catalyst
loading is developed toward reductive cleavage of isoxazo-
line, carbonyl azide and domino cyclization to furnish valu-
able 2-hydroxy-4-keto esters, primary amides and a new
class of heterocycle, 4-hydroxy-2-pyrroline-5-one.
(II, Scheme 1) is constructed in a water medium by utilizing
inexpensive CuSO4·5H2O, SDS and ascorbic acid. Cu(0)-NPs
are fabricated (III) inside the cooperative assembly by reduction
of CuSO4, nucleation, growth and quenching at 60 °C.
For clarity, surfactants are removed from the top portion of the
NPs (III, Scheme 1). The major problem of the insolubility of
the hydrophobic phase organic precursor in the water medium is
solved by the construction of a surfactant surrounded lipophilic
environment (III). Small Cu(0)-NPs are fabricated by reducing
Cu(AOT)2 with NaBH4 (or N2H4) in AOT reverse micelle (size:
∼20 nm)9b and also using nanoporous SBA-15 (3 nm).9d
We have avoided using strong reducing agents which are
harmful to most reduction prone organic functionalities. In this
context, the reflux synthesis of Cu(0)-NPs is encouraging.9c The
morphology of the nanoreactor is determined by SEM imaging
(dimension: 90–110 nm, panel a, Fig. 1). Routine characteriza-
tion of the Cu(0)-NPs is performed by means of UV-vis studies
[plasmone peak: 586 nm, panel b), DLS study (7.8 nm, panel c),
TEM imaging (histogram: 2–7 nm, panel d) and comparing the
literature X-ray diffraction pattern [peaks at (2θ): 43.4°, 50.4°,
73.9°, 90.0° and 95.7°, panel e].10
Water is the solvent of a magnificent array of reactions taking
place in our body for keeping it healthy and functioning. Water
is inevitable for selective formation of new bonds during biosyn-
thesis of small molecules and multistep synthesis of macromole-
cules.1 These outstanding properties of water are due to its
unique structure, both acidic (H3O+) and basic (HO−) nature,
strong hydrogen bonding, high polarity, dielectric constant,
surface tension and heat capacity. Although, Wohler’s use of
water as a medium for the synthesis of urea has been known for
many years, scientists of academic and industrial settings are
now exploring the possibility of replacing large volumes of toxic
organic solvents by water as the reaction medium toward the
development of cleaner and green processes.2 To avoid toxic
organic solvents, highly reactive metal-NPs3,4 can be employed
as efficient catalysts for organic synthesis in a water medium.
Although, it is very difficult for a chemist to use water as a
medium for the fabrication of small metal-NPs and the simulta-
neous development of their outstanding catalytic activity toward
fundamental organic transformation.
Next, we turned our attention to the development and
optimization of the catalytic reduction property of the metal
Cu(0)-NPs. After extensive studies, reductive cleavage (Table 1)
of ethyl 3-naphthylisoxazoline-5-carboxylate (1a) to ethyl
2-hydroxy-4-keto-4-naphthylbutyrate (2a, entry 1, Table 1) is
optimized with very low catalyst loading (0.6 mol%) and good
yield (84%, entry 1, Table 2). Product 2a is not detected if the
Nitrile oxide cycloaddition5–8 derived Δ2-isoxazoline repre-
sents a responsive heterocyclic scaffold for the total synthesis
of natural products and valuable synthons.6 On treatment of
the appropriate reagents, the cycloadduct provides easy access to
3-amino alcohols, allyl alcohols, 1,3-diols, hydroxy ketones,
1,3-diketones, enones, 1,6-diketones, 1,3-dienes and other
diversely functionalized synthons.6a,7,8 In addition to existing
methods, in this communication we report another frontier for its
synthetic application by devising a simple catalytic reduction
strategy in a water medium involving in situ fabricated
aDepartment of Chemistry, University of Calcutta, University College of
Science, 92, A. P. C. Road, Kolkata-700009, India
bSree Chaitanya College, Habra-743268, India. E-mail: dkmchem@
caluniv.ac.in, mitatanu@gmail.com; Fax: +91-33-2351-9755;
Tel: +91-33-2350-9937
†Electronic supplementary information (ESI) available: procedures,
characterization data, spectra. See DOI: 10.1039/c2gc35252d
Scheme 1 Fabrication of Cu(0)-NPs and their catalytic activity.
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Our fabricated Cu(0)-NPs in a water medium chemoselectively
reduced functionalized Δ2-isoxazolines (1a–i) possessing an
ester functionality to afford valuable 2-hydroxy-4-keto ester
synthons (2a–h, Table 2) with fast reaction convergence
(3.5–5.0 h) and good yields (79–89%). In the presence of water,
the reduction property of the surface electrons13 is significantly
enhanced because water is used as the electron carrier for the
reduction of the N–O bond of the cycloadduct. Expectantly, a
very low catalyst loading (0.6 mol%) of Cu(0)-NPs is found to
be active due to the formation of an ideal reaction system of
Cu(0)-NPs possessing highly active surfaces with surrounding
water molecules as an electron carrier. Dehalogenation is one of
the major concerns of reduction processes, involving hydride
and metal catalyzed hydrogenation reactions. Herein, the mild
Cu(0)-NPs catalyzed process does not remove the halogens
(F, Cl or Br, entries 3, 7, 8, Table 2). Activated phenyl, naphthyl
and heterocyclic aromatic nuclei are also tolerated in this chemo-
selective reduction process.
Metal catalyzed ring opening and domino or sequential cycli-
zation strategies are becoming important tools for the synthesis
of difficult to access hetero- and carbocyclic frameworks.14
Herein, we disclose our novel studies on the domino cyclization
process by the Cu(0)-NPs (path b, Scheme 2). Interestingly, on
treatment of Δ2-isoxazoline-5-esters (1a) at an elevated tempera-
ture (80 °C), the reductive process has furnished 4-hydroxy-2-
pyrroline-5-one (3a) along with traces of the corresponding
β-hydroxy ketone (2a). Pyrrolinone compounds are found to be
peptidomimetics and anti-HIV agents.15 Only 0.6 mol% of
CuSO4·5H2O is required for rapid (3.5–4.0 h) ring opening and
domino cyclization to afford the new class of γ-hydroxy pyrroli-
nones (3a–g, Table 2) in high yields (80–89%). Involvement of
the ester group in the catalytic domino cyclization process is
verified by using two isoxazoline precursors possessing different
ester groups (methyl and ethyl, 1a and 1b, entries 1 and 2,
Table 2) which has furnished the same heterocycle 3a.
The reaction is presumed to proceed via the predominant acti-
vation and reductive cleavage of the heteroatomic N–O bond
by electron transfer16 from the highly active surface of the
Cu(0)-NPs involving water clusters to form a stable Cu+2-
chelated six membered intermediate IV. It, on protonation and
subsequent Cu+2-assisted removal of ammonia (V), provides 2
(path a, Scheme 2). On the other hand, intermediate IV at a
higher temperature (80 °C) is expected to undergo domino cycli-
zation involving the CvO group of the ester functionality to
form a seven-membered intermediate, VI, which is subsequently
transformed into γ-hydroxy pyrrolinone (3, path b) via the for-
mation of a putative five-membered cyclic intermediate VII. The
Cu(0)-NPs are regenerated from Cu+2, which involves the con-
struction of the nanoreactor (III, Scheme 1).
Fig. 1 (a) SEM image of the cooperative assembly. (b) UV-vis spec-
trum. (c) DLS data. (d) TEM image. (e) Powder XRD data.
Table 1 Development and optimization of the reaction
Catalyst
Entry (mol%)
Reagents and reaction Conversion
Yield
(%)
conditionsa,b
(%)
1
CuSO4 (0.6) 1a, AA, SDS, 60 °C,
4 h
CuSO4 (0.6) 1a, AA, SDS, rt, 24 h
CuSO4 (0.6) 1a, AA, 60 °C, 12 h
100
2a, 84
2
3
4
0
0
0
2a, ndc
2a, nd
2a, nd
—
1a, AA, SDS, 60 °C,
12 h
5
Cu dust
(200)d
1a, AA, 60 °C, 12 h
0
2a, nd
6
7
CuOTf (10)
Cu
1a, AA, 60 °C, 12 h
1a, AA, 60 °C, 12 h
0
0
2a, nd
2a, nd
(OTf)2(10)
8
9
CuSO4 (0.6) 1a, AA, SDS, EDCe,
60 °C, 12 h
0
2a, nd
3a, 89
CuSO4 (0.6) 1a, AA, SDS, 80 °C,
4.0 h
100
a Ascorbic acid (1 mmol). b Sodium dodecylsulfonate (20 mol%). c Not
detected. d Bulk copper powder. e Ethylenedichloride.
reaction is conducted at ambient temperature, without surfactant
SDS or CuSO4·5H2O (entries 2–4, Table 1). The results in
Table 1 reveal that the in situ fabricated Cu(0)-NPs (entry 1,
Table 1) are efficient compared to bulk Cu(0), Cu(I) and Cu(II)
(entries 5–7, Table 1). Due to the absence of the hydrated form
of Cu(0)-NPs, the reaction is unsuccessful in organic solvent
(entry 8, Table 1). On enhancement of the temperature to 80 °C,
a new class of heterocycle, 4-hydroxy-5-keto-2-pyrroline (3a) is
furnished (entry 9, Table 1).
Selective activation of N–O bond and its reductive cleavage
are important process for both biochemical and chemical
synthesis of valuable compounds.11 RANEY Ni–H2 in aqueous
acetic acid,12 SmI2/B(OH)3/0 °C7a and Fe(10 equiv.)/NH4Cl/
EtOH–H2O(1 : 1)/80 °C7b are employed for the reduction of
Δ2-isoxazoline to achieve valuable β-hydroxy ketone synthons.
Many natural products and functional molecules possess a
primary amide as a crucial functionality and have found a broad
spectrum of applications in energetically viable aggregated
materials, construction of cell surface-active N-glycosyl peptides,
novel functionalities and valuable heterocycles.17 Application of
the robust catalytic system is extended for the homoatomic
reductive-cleavage of the N–N bond (VIII and IX) in carbonyl-
azide (4) to afford valuable primary amides (5a–j, Scheme 3)
with fast reaction rates (1.5–2.0 h) and high yields (79–95%).
The performance of our benign method is evaluated by the
1590 | Green Chem., 2012, 14, 1589–1592
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Table 2 Synthesized β-hydroxyketone and γ-hydroxypyrrolinone
Entry
Isoxazoline (1)
Time (h)
2, yield (%)
β-Hydroxy ketone (2)
Time (h)
3, yield (%)
γ-Hydroxy pyrrolinone (3)
1
2
3.5
3.5
2a, 84
2b, 89
3.5
3.5
3a, 89
3a, 88
3
4.0
2c, 88
4.0
3b, 88
4
5
6
4.0
4.0
4.5
2d, 79
2e, 83
2f, 82
4.0
4.0
4.5
3c, 85
3d, 83
3e, 85
7
8
4.0
5.0
2g, 81
2h, 83
3.5
3.5
3f, 81
3g, 80
Scheme 2 Possible reaction paths.
Scheme 3 Reduction of carbonyl azides to primary amides.
reduction of carbonyl azides bearing electron donating, electron
withdrawing, halogens and π-bonds to afford functionalized
amides with an extremely low catalyst loading (0.2 mol%).
We have recovered SDS (82%) from the concentrated aqueous
solution by crystallization. Recovered Cu(0)-NPs are less
efficient because a higher catalytic loading (3%) is required for
the reduction process.
Notes and references
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Nature, 2005, 435, 746.
In conclusion, we have developed robust catalytic reduction
properties of in situ fabricated small Cu(0)-NPs in water medium
toward the heteroatomic cleavage of N–O bonds, homoatomic
N–N bonds and domino cyclizations to afford 2-hydroxy-4-keto
ester synthons, valuable primary amides and a new class of
heterocycle, 4-hydroxy-2-pyrroline-5-one.
Financial support from DST (SR/NM/NS-29/2010 and SR/S1/
OC-22/2006), CRNN, CSIR-SPMF (K. S. G.) and CSIR-SRF
(T. S.) of India are gratefully acknowledged.
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