A mild oxidative method for the preparation of γ-hydroxy-α-nitroolefins from α,β-epoxyketoximes using IBX

Article abstract of DOI:10.1016/j.tetlet.2009.10.090

An efficient method for the preparation of γ-hydroxy-α-nitroolefins from α,β-epoxyketoximes has been developed using IBX. The reaction occurs at room temperature without the formation of over-oxidation products and also has an easy work-up procedure.

Full text of DOI:10.1016/j.tetlet.2009.10.090

Tetrahedron Letters 50 (2009) 7395–7398
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild oxidative method for the preparation of
from ,b-epoxyketoximes using IBX
c-hydroxy-a-nitroolefins
a
*
*
Alba Souto, Jaime Rodríguez , Carlos Jiménez
Departamento de Química Fundamental, Facultade de Ciencias, Campus da Zapateira, Universidade da Coruña, 15071 A Coruña, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the preparation of c-hydroxy-a-nitroolefins from a,b-epoxyketoximes has been
developed using IBX. The reaction occurs at room temperature without the formation of over-oxidation
products and also has an easy work-up procedure.
Received 21 September 2009
Revised 15 October 2009
Accepted 19 October 2009
Available online 23 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a,b-Epoxyketoximes
c
-Hydroxy- -nitroolefins
a
Oxidation
Hypervalent iodine
IBX
DMP
The nitro group is particularly versatile in synthesis as it can be
transformed into a plethora of functionalities. The Nef reaction,
nucleophilic displacement, reduction to an amino group and con-
version into a nitrile oxide are only some examples of the possible
transformations.1 More specifically, conjugated nitroolefins have
found numerous applications in organic synthesis.2 The character
of these systems as electron-deficient alkenes allows easy 1,4-
addition reactions and this opens the way to synthetically useful
C–C and C–X (X = N, O) bond-forming reactions.3 These compounds
are also powerful dienophiles or dipolarophiles in cycloaddition
reactions to generate new carbon–carbon single or double bonds.
A number of methods have already been developed for the prepa-
ration of nitroolefins, such as the nitroaldol (Henry) reaction,4 but
there is considerable interest in developing new and simple meth-
ods for the preparation of this type of compound.
On the other hand, organic derivatives of hypervalent iodine re-
agents have found extensive applications in synthetic organic
chemistry because of their selectivity, efficiency and simplicity of
use.5 Among these compounds, 2-iodoxybenzoic acid (IBX) is
becoming the reagent of choice due to its ease of handling, stabil-
ity/longer shelf life, tolerance to moisture and zero toxic waste
generation. IBX was initially used for the oxidation of alcohols to
carbonyl compounds,6 but its synthetic value has been extended
to a variety of other useful transformations.7
The oxidative conversion of oximes into nitro functions using tri-
fluoroperoxyacetic acid was reported a long time ago.8 Some years
later Takamoto et al. reported the transformation of
a,b-epoxyke-
toximes to -hydroxy-
c
a
-nitroolefins using the same reagent.9 The
products were employed for the synthesis of 3-nitrocycloalkenones
for use as dienophiles.10 Furthermore, the oxidative elimination of
a
-haloketoximes using trifluoroperoxyacetic acid to give a-nitro-
olefins has been reported.11 However, the wider reactivity of the tri-
fluoroperoxyacetic acid (Baeyer–Villiger oxidation, epoxidation of
alkenes, etc.) narrowed the applications of this reagent in that chem-
ical transformation.
We report here a new oxidative method for the conversion of
a,b-epoxyketoxime compounds to c-hydroxy-a-nitroolefins in
good to moderate yields. The method employs IBX as a very mild
oxidant that overcomes some of the disadvantages associated with
the use of trifluoroperoxyacetic acid. Our method can be character-
ised by two striking features: (a) easy work-up procedure, (b) the
reaction occurs at room temperature without the formation of
* Corresponding authors. Tel.: +34 981 167000; fax: +34 981 167065.
E-mail addresses: jaimer@udc.es (J. Rodríguez), carlosjg@udc.es (C. Jiménez).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.090

7396
A. Souto et al. / Tetrahedron Letters 50 (2009) 7395–7398
Table 1
Effect of oxidant, additives and reaction conditions on yield
Oxidant (equiv)
Additive
Solvent/T (°C)
Product
Time (h)
Yield (%)
DMP (1.1)
IBX (2.5)
IBX (3.0)
IBX (1.5)
Thiourea (0.2 equiv)/CH3COONa (1.0 equiv)
—
TEAB (3.0 equiv)
NMO (1.5 equiv)
CH3CN/0
CH3CN/60
CH3CN/60
DMSO/rt
2
8.5
0.5
0.5
24
71
—
20
81
Complex mixture
2 and
2
a
-hydroxyisophorone (4:5)
over-oxidation products as a result of the high chemoselectivity
and the mild nature of IBX. To the best of our knowledge, the appli-
additives. Although DMP and IBX are suitable for this chemical
transformation, IBX has become the reagent of choice because it
is cheaper and more widely available.14 The use of a standard sol-
vent (such as acetonitrile) in conjunction with IBX was not fruitful
(Table 1). On the basis of the studies performed, the optimum con-
ditions involved carrying the reaction out in DMSO in the presence
of 1.5 equiv of IBX and N-methylmorpholine-N-oxide (NMO) as an
additive at room temperature for 24 h.15
cability of IBX in the preparation of
,b-epoxyketoximes has not been reported previously.
During our studies directed at the synthesis of several
c-hydroxy-a-nitroolefins from
a
hydroximinosteroids as antitumour agents,12 we observed that
3b,4b-dihydroxy-6-nitrocholest-5-ene was formed when 4b,5b-
epoxy-3b-hydroxy-6E-hydroximinocholestane was treated with
Dess–Martin Periodinane (DMP) in CH2Cl2 (Scheme 1). The chemical
structure of the product was deduced from its NMR spectra and MS
data.13
The scope and limitations of our new method for the synthesis
of these nitroolefins were studied by preparing a variety of other
compounds using the optimised conditions. The
yketoxime starting materials were prepared from their corre-
sponding ,b-unsaturated ketones by treatment with H2O2 in
a,b-epox-
We then investigated the action of DMP and IBX on a variety of
structurally simplified
reaction.
a,b-epoxyketoximes in order to study this
a
basic media followed by oximination with NH2OH. The results
are summarised in Table 2. Good yields were obtained with epox-
yketoximes generating tertiary hydroxy derivatives except in the
Initial studies were carried out using epoxyisophorone oxime as
a model substrate with variations in the solvent, temperature and
Table 2
Oxidative conversion of
a,b-epoxyketoximes to c-hydroxy-a-nitroolefins with IBX/NMO in DMSO
Entry
Substrate
Producta,b
Yieldc (%)
81
1
2
3
74d
41
4
5
52
0
6
91
a
Structures were confirmed from their NMR and MS data.
Spectral data for compounds which have not been reported previously are given in Ref. 19.
Yields of products isolated after column chromatography.
b
c
d
Diastereoisomeric mixture in a ratio (5:1).

A. Souto et al. / Tetrahedron Letters 50 (2009) 7395–7398
7397
case of exocyclic (entry 3) and acyclic (entry 4) epoxides. A com-
plex mixture including some trace of starting material is observed
in the 1H and 13C NMR spectra of the reaction product correspond-
ing to entry 5, probably because the epoxyketoxime is acylic and
the hydroxylated derivative would be secondary.
to
mation of ketoximes with DMP is hampered by the presence of a
good leaving group at the -position as this leads to the corre-
sponding conjugated nitrolefins instead of regeneration of the ke-
tone. Further research on this reaction is underway.
c-hydroxy-a-nitroolefins using this transformation. The deoxi-
a
Although detailed mechanistic studies have not been carried
out, a plausible mechanism for the IBX reaction is presented in
Scheme 2. We suggest that the reaction proceeds through the for-
mation of an intermediate by the direct attack of the nitrogen atom
to iodine, which would then evolve to form the O@N double bond
to originate the nitro functionality, opening of the epoxy group to
Acknowledgements
This work was financially supported by Grants from the Minis-
try of Science and Innovation of Spain (CTQ2008-04024 and
AGL2009-12266-C02-02).
generate a hydroxyl group at the
c-position and the subsequent
expulsion of iodosobenzoic acid (IBA). In fact, during the work-
up, the formation of a white precipitate, which was mainly com-
posed of IBA, was indicative of a successful result.16 Additionally,
this mechanism is supported by the proposal that the formation
of an NMOÁIBX complex in DMSO improves the reactivity.17 Inter-
estingly, it has been reported that IBX and DMP oxidatively deox-
imate ketoximes smoothly at room temperature in very high
yields.18 Thus, we anticipated that the treatment of oximes bearing
References and notes
1. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: Weinheim, 2001.
2. (a) Barret, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751–762; (b) Ballini, R.;
Marcantoni, E.; Petrini, M. In Amino Group Chemistry; Ricci, A., Ed.; Wiley-VCH,
2008; pp 93–148.
3. (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–1894; (b)
Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem. 1992, 57, 2160–2162.
4. (a) Ono, N. In Nitro Compounds; Recent Advances in Synthesis and Chemistry;
Feuer, H., Nielsen, A. T., Eds.; VCH: New York, 1990; (b) Luzzio, F. A. Tetrahedron
2001, 57, 915–945; (c) Hübner, J.; Liebscher, J.; Pätzel, M. Tetrahedron 2002, 58,
10485–10500; (d) Jovel, I.; Prateeptongkum, S.; Jackstell, R.; Vogl, N.;
Weckbecker, C.; Beller, M. Adv. Synth. Catal. 2008, 350, 2493–2497.
5. Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: San Diego,
1996.
6. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022.
7. For reviews, see: (a) Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812–2814; (b)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584; (c) Kumar, I.
Synlett 2005, 1488–1489; (d) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–
3665.
8. (a) Emmoms, W. D.; Pagano, A. S. J. Am. Chem. Soc. 1955, 77, 4557–4559; (b)
Sundberg, R. J.; Bukowick, P. A. J. Org. Chem. 1968, 33, 4098–4102.
9. (a) Takamoto, T.; Ikeda, Y.; Tachimori, Y.; Seta, A.; Sudoh, R. J. Chem. Soc., Chem.
Commun. 1978, 350–351; (b) Burke, S.; Danheiser, R.L., Handbook of Reagents
for Organic Synthesis-Oxidizing and Reducing Agents, John Wiley & Sons: New
York, 2001.
a good leaving group at the
a-position with a hypervalent iodine
reagent such as DMP or IBX favours the formation of the nitroolefin
rather than the regeneration of the ketone.
This hypothesis would also explain the transformation of an a-
acetoxyoxime to a nitroolefin using DMP reported by Ganem and
co-workers to obtain 2-nitroglycals.20 In an effort to find evidence
for this process, we carried out the reaction of two 2-chlorooximes
with DMP. Treatment of 2-chlorocyclohexanone oxime or 2-chlo-
rocyclopentanone with DMP at 0 °C gave the corresponding nitro-
olefins (Scheme 3) without the regeneration of the carbonyl group,
a finding that is consistent with the aforementioned hypothesis.
In summary, we have found that IBX is an efficient oxidant for
the conversion of
hydroxy- -nitroolefins. This transformation is also possible using
DMP. Thus, ,b-unsaturated carbonyl compounds can be converted
a,b-epoxyketoximes to their corresponding c-
10. Corey, E. J.; Estreicher, H. Tetrahedron Lett. 1981, 22, 603–606.
11. Sakakibara, T.; Ikeda, Y.; Sudoh, R. Bull. Chem. Soc. Jpn. 1982, 55, 635–636.
12. Poza, J.; Rega, M.; Paz, V.; Alonso, B.; Rodríguez, J.; Nélida, S.; Fernández, A.;
Jiménez, C. Bioorg. Med. Chem. 2007, 15, 4722–4740.
a
a
13. Spectral data: 1H NMR (200 MHz, CDCl3) dH: 4.40 (d, J = 3.5 Hz, 1H), 3.47 (br d,
J = 10.6 Hz, 1H), 2.36 (d, J = 1.9 Hz, 1H), 2.32 (d, J = 4.1 Hz, 1H), 2.04 (td, J = 12.4
and 3.1 Hz, 1H), 1.28 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H), 0.68
(s, 3H); 13C NMR (50 MHz, CDCl3) dC: 149.90 (s), 140.36 (s), 71.00 (d), 68.03 (d),
56.21 (d), 55.94 (d), 48.90 (d), 42.33 (s), 39.44 (t), 39.26 (t), 37.14 (s), 36.08 (t),
35.68 (t), 35.68 (s), 33.32 (t), 31.59 (d), 28.06 (t), 27.96 (d), 24.45 (t), 24.01 (t),
23.79 (t), 22.77 (q), 22.52 (q), 21.39 (q), 20.37 (t), 18.64 (q), 11.78 (q). (+)-
LRESIMS m/z (%): 470 ([M+Na]+, 36).
14. Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141–152.
15. General experimental procedure:
A mixture of IBX (1.5 equiv) and NMO
(1.5 equiv) was dissolved in dry DMSO by stirring at room temperature until
complete dissolution (ꢀ15 min), that is until the suspension becomes
transparent. To this solution was added the a,b-epoxyketoxime (1 equiv) and
the mixture was stirred vigorously at the same temperature until completion
of the reaction, which was monitored by thin-layer chromatography. The
reaction mixture was diluted with an equal volume of aqueous NaHCO3 (5%),
filtered through a pad of Celite and extracted with diethyl ether for three times.
The combined organic phase was washed with saturated NaHCO3 solution,
water, brine and dried (MgSO4). Evaporation of the solvent left the crude
product, which was in some cases further purified by column chromatography
on silica gel to provide the pure
c-hydroxy-a-nitroolefin. All products were
characterised by 1H NMR, 13C NMR and MS, and identified in some cases by
comparison with reported values.
16. Kirsch, S. F. J. Org. Chem. 2005, 70, 10210–10212.
17. Nicolau, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993–
996.
Scheme 2. Plausible mechanism for the formation of
from ,b-epoxyketoximes.
c-hydroxy-a-nitroolefins
a
18. (a) Krishnaveni, N. S.; Surendra, K.; Nageswar, Y. V. D.; Rao, K. R. Synthesis 2003,
1968–1970; (b) Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760–764.
19. Nitroolefins from verbenone (entry 2): Major isomer: 1H NMR (300 MHz, CDCl3)
d 6.78 (t, J = 1.8 Hz, 1H), 3.18 (td, J = 5.7, 1.7 Hz, 1H), 2.61 (dt, J = 10.7, 5.7 Hz,
1H), 2.10 (td, J = 5.7, 1.7 Hz, 1H), 1.63 (d, J = 10.7 Hz, 1H), 1.48 (s, 6H), 0.94 (s,
3H); 13C NMR (75 MHz, CDCl3) d 158.08 (s), 130.99 (d), 71.91 (s), 53.12 (d),
47.73 (s), 42.98 (d), 32.28 (t), 26.74 (q), 25.87 (q), 23.44 (q); minor isomer: 1H
NMR (300 MHz, CDCl3) d 6.78 (t, J = 1.8 Hz, 1H), 3.06 (br t, J = 5.6 Hz, 1H), 2.41–
2.29 (m, 1H), 1.84 (s, 1H), 1.69 (s, 1H), 1-44 (s,3H), 1-42 (s,3H), 1.01 (s, 3H). 13C
NMR (75 MHz, CDCl3) d 158.08 (s), 130.99 (d), 61.98 (s), 52.57 (d), 47.73 (s),
41.36 (d), 29.67 (t), 26.74 (q), 25.87 (q), 23.44 (q); (À)-HRESIMS m/z: 196.0971
[MÀH]À, (calcd for C10H14NO3, 196.0979). Nitroolefin from pulegone (entry 3):
1H NMR (300 MHz, CDCl3) d 2.66–2.55 (m, 1H), 2.19–2.11 (m, 2H), 2.06 (m, 1H),
1.91 (brs, 1H), 1.78 (m, 2H), 1.42 (s, 3H), 1.36 (s, 3H), 1.01 (d, J = 6.5 Hz, 3H). 13C
Scheme 3.

7398
A. Souto et al. / Tetrahedron Letters 50 (2009) 7395–7398
NMR (75 MHz, CDCl3) d 144.20 (s), 136.87 (s), 73.28 (s), 36.71 (t), 29.99 (t),
(d), 42.41 (s), 39.62 (t), 39.47 (t), 38.80 (s), 36.09 (t), 35.71 (d), 35.47 (t), 34.79
(d), 28.76 (t), 28.12 (t), 27.98 (d), 27.45 (t), 24.09 (t), 23.79 (t), 22.77 (q), 22.57
(q), 22.25 (t), 21.06 (t), 18.64 (q), 15.54 (q), 11.86 (q); (+)-LRFABMS m/z: 432
([M+H]+, 5), 416 ([MÀO+H]+, 15), 385 (100); (+)-HRESIMS m/z: 416.3506
[MÀO+H]+, (calcd for C27H46NO2, 416.3523).
28.58 (q), 28.58 (q), 28.28 (d), 26.12 (t), 20.81 (q); (+)-HRESIMS m/z: 222.1101
[M+Na]+, (calcd for C10H17NNaO3, 222.1100). Nitroolefin from cholesterol
derivative (entry 6): 1H NMR (300 MHz, CDCl3) d 6.99 (d, J = 1.8 Hz, 1H), 1.03
(s, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H), 0.68 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 151.38 (s), 136.43 (d), 72.60 (s), 56.06 (d), 55.92 (d), 43.54
20. Clark, M. A.; Wang, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 347–349.