Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones with Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.orglett.5b02029

Hypervalent iodine compounds are viable reagents for the oxidation of N,N-disubstituted hydroxylamines to the corresponding nitrones, with IBX performing best. The procedure is very simple and user-friendly and affords the target compounds with high effic

Full text of DOI:10.1021/acs.orglett.5b02029

Letter
pubs.acs.org/OrgLett
Oxidation of N,N‑Disubstituted Hydroxylamines to Nitrones with
Hypervalent Iodine Reagents
Camilla Matassini,† Camilla Parmeggiani,‡,† Francesca Cardona,† and Andrea Goti*,†
†Dipartimento di Chimica “Ugo Schiff”, Polo Scientifico e Tecnologico, Universita
̀
di Firenze, Via della Lastruccia 13, 50019 Sesto
Fiorentino (FI), Italy
‡CNR−INO and LENS, via N. Carrara 1, 50019 Sesto Fiorentino (FI), Italy
S
* Supporting Information
ABSTRACT: Hypervalent iodine compounds are viable
reagents for the oxidation of N,N-disubstituted hydroxylamines
to the corresponding nitrones, with IBX performing best. The
procedure is very simple and user-friendly and affords the
target compounds with high efficiency and regioselectivity,
highlighting IBX as the reagent of choice for preparation of
aldonitrones from nonsymmetric hydroxylamines. Evidence for
a mechanism involving nitrogen to iodine coordination has been collected.
ypervalent iodine reagents, both of the λ3 and λ5 type,1
serve our aim in the search for a novel and convenient metal-free
Hhave been established as efficient and useful reagents for synthesis of nitrones.11 IBX,12 which is also able to oxidize
alcohols and has been used to replace DMP in some
applications,13 was also considered a good candidate. Moreover,
IBX has emerged recently as a very versatile oxidant14 and has
been investigated by the Nicolaou group as an oxidant for
nitrogenated compounds.15 Particularly, analogously to the
behavior of NMO/TPAP,16 it was found to oxidize effectively
secondary amines to the corresponding imines. Efficient
oxidations of N-benzylhydroxylamine and N,O-dibenzylhydrox-
ylamine to the corresponding oximes were also described;15
however, no example of N,N-disubstituted hydroxylamines as
substrates was reported. Finally, DIB was taken into account, as
an example of an I(III) oxidant. It was also taken into
consideration because of its use as an efficient reagent for the
related generation of nitrile oxides from the corresponding
oximes, as recently reported by Ciufolini and co-workers.17,18
In this Letter we report our results on the oxidation of N,N-
disubstituted hydroxylamines to the corresponding nitrones by
the hypervalent iodine oxidants 1−3, which show IBX as the
reagent of choice, with high efficiency and uncommon
potentialities for the regioselective oxidation of nonsymmetric
hydroxylamines, particularly in the preferential formation of
aldo- vs keto-nitrones.
the oxidation of several organic functional groups. Among the
former type, (diacetoxyiodo)benzene (DIB, 1) is the most
popular and employed member, while Dess-Martin periodinane
(DMP, 2) and o-iodoxybenzoic acid (IBX, 3) have been most
extensively studied and used as I(V) oxidants (Figure 1).
Figure 1. Common commercially available hypervalent iodine oxidizing
agents.
For many years, we have been strongly involved in the use of
nitrones as useful and versatile synthetic intermediates for the
obtainment of alkaloids and other nitrogenated products.2
Moreover, nitrones are widely used for biological studies as
spin trapping reagents and antioxidants in age related diseases.3
In this context, we have diffusely investigated new simple and
practical metal-catalyzed oxidative procedures, with the use of
inexpensive oxidants, for the synthesis of nitrones from different
nitrogenated precursors,4 such as secondary amines,5 imines,6
and N,N-disubstituted hydroxylamines.7 During these studies,
we have observed that common reagents used for the
interconversion of alcohols to the corresponding carbonyl
derivatives, such as NMO/TPAP, are also able to oxidize N,N-
disubstituted hydroxylamines to the corresponding nitrones
under mild conditions with high chemoselectivity and without
formation of byproducts.8 We therefore envisaged that DMP,9
one of the currently most used reagents for the mild oxidation of
alcohols to aldehydes and ketones,10 was a suitable candidate to
We initially tested the iodine hypervalent oxidants 1−3 in the
oxidation of simple unfunctionalized and symmetric hydroxyl-
amines 4−6 under the same standard reaction conditions in
order to compare the efficiency of the three reagents in the
desired transformation (Table 1).
The results of oxidation of hydroxylamines 4−6 show that all
three reagents 1−3 perform successfully, affording complete
conversions after 2 h in dichloromethane at rt and giving nitrones
Received: July 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02029
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Table 1. Evaluation of Hypervalent Iodine Oxidants 1−3 in
Table 2. Evaluation of Hypervalent Iodine Oxidants 1−3 in
a
a
the Oxidation of Hydroxylamines to Nitrones
the Oxidation of Carbohydrate Derived Hydroxylamines
a
Reaction conditions: hydroxylamine (0.25 mmol) in 0.09 M dry
b
CH2Cl2, oxidant (1.5 equiv), rt, 2 h. Isolated yield after flash column
chromatography, unless otherwise stated. Yield of crude product
c
(>98% purity).
7−9 in good to excellent yields. IBX stems as the best oxidant;
besides the higher yields, a greater advantage is represented by
the much easier workup. For example, nitrone 7 was obtained
spectroscopically pure in 95% yield by a simple extraction and no
further separation was required. Use of a lower amount of IBX
was less efficient: oxidation of hydroxylamine 4 required 6 h to go
to completion with 1.1 of equiv IBX (91% yield) and afforded
only 75% conversion after 24 h with 0.6 equiv of IBX.
Notwithstanding IBX appearing optimal, use of DIB as the
oxidant is also worth considering due to its lower cost.
a
Reaction conditions: hydroxylamine (0.2 mmol) in 0.09 M dry
b
CH2Cl2, oxidant (1.5 equiv), rt, 2 h. Determined by integration of 1H
In order to check the behavior of the three iodine hypervalent
reagents toward structurally more complex substrates, we
extended our study to carbohydrate derived hydroxylamines
10−13, which contain different hydroxyl protecting groups, such
as acetonide and benzyl, and are unsymmetric. Consequently,
two regioisomeric nitrones, an aldonitrone a and a ketonitrone b,
may originate by dehydrogenation of the less substituted or the
more substituted α carbon atom, respectively. The issue of
regioselectivity in the oxidation of unsymmetric hydroxylamines
is still an unmet goal, apart from a few peculiar substrates. The
results of oxidation of hydroxylamines 10, 11, 12, and 13 under
the same standard conditions are reported in Table 2 in entries 1,
2, 3, and 4, respectively.
These results clearly establish IBX as a superior oxidant for the
studied transformation, affording nearly quantitative yields of
nitrones also from more challenging functionalized hydroxyl-
amines 10−13 with no loss of stereochemical integrity.
Conversely, DMP and DIB performed poorly with these
substrates, showing complete conversion but scarce chemo-
selectivity. Moreover, IBX furnished aldonitrones as major
products with considerable regioselectivity, ranging from
moderate for hydroxylamines 11 and 13 (Table 2, entries 2
and 4) to complete for 10 and 12 (Table 2, entries 1 and 3).
While the complete regioselectivity for 10 was expected since it
was also observed with MnO2,19 high regioselectivity for
hydroxylamines 11−13 has no precedent in related cases. In
this respect, the behavior of IBX appears unique, since the other
hypervalent iodine reagents display poor, if any, regioselectivity.
In order to compare the regioselectivity shown by IBX with that
NMR spectrum of the crude reaction mixture, unless otherwise stated.
c
Isolated yield after flash column chromatography, unless otherwise
d
e
stated. Yield of crude product (>98% purity). Determined on the
basis of isolated yield after flash column chromatography.
of other typical oxidants for hydroxylamines, compound 13 was
oxidized with a variety of reagents (Table 3). All the tested
reagents afforded nearly quantitative yields of the two nitrones
17a,b, but their ratio varied considerably, as well as the time
Table 3. Evaluation of the Aldonitrone/Ketonitrone
Regioselectivity in the Oxidation of Hydroxylamine 13 with
Several Reagents
17a/17b
a
entry
oxidant
reaction conditions
ratio
1
2
3
4
5
HgO
CH2Cl2, rt, 74 h
CH2Cl2, rt, 2 min
CH3CN, rt, 20 h
CH2Cl2, rt, 7 d
CH2Cl2, rt, 2 h
1:1
1:1
DDQ
TPAP/NMO
1:2
5% NaClO, aq. 0.5 M KHSO4
IBX
5.9:1
5:1
a
Determined by integration of 1H NMR spectrum of the crude
reaction mixture.
B
DOI: 10.1021/acs.orglett.5b02029
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Organic Letters
Letter
required for completion of the reaction. While HgO and DDQ
gave approximately an equimolar amount of the two
regioisomeric nitrones (Table 3, entries 1 and 2), TPAP/
NMO8 favored formation of the ketonitrone 17b (entry 3).
Considerable regioselectivity in favor of the aldonitrone 17a
(entry 4) was obtained by the use of bleach in acidic media (pH ≈
2.8), conditions which were found to speed up the oxidation and
slightly favor formation of aldo- vs ketonitrones.11a However, this
oxidation required long reaction times and gave erratic results,
showing low reproducibility. A similar rewarding 5:1 selectivity
was obtained with the very reliable and simple oxidation with IBX
(entry 5).
Table 4. Oxidation of Unsymmetric Acyclic and Cyclic
Hydroxylamines with IBX
a
The above results demonstrate that IBX is the reagent of
choice for the oxidation of hydroxylamines to nitrones among the
common hypervalent iodine oxidants, and suggest it may possess
unique and superior properties for attaining high regioisomeric
ratios from unsymmetric hydroxylamines. In this respect, we
checked further the chemo- and regioselectivity of the oxidation
with IBX with other unsymmetric hydroxylamines 18−23, either
cyclic or acyclic (Table 4), and possessing the same (entries 1−3)
or different (entries 4−6) degree of substitution at the two
carbon atoms adjacent to nitrogen. The hydroxylamine 18
afforded quantitatively an equimolar mixture of the two
regioisomeric nitrones 24 (entry 1), suggesting that thermody-
namic stability of the products does not play a significant role.
The two protected 1-hydroxypyrrolidin-3-ols 19 and 20 gave the
nitrones 25a and 26a, respectively, in significant excess with
respect to their regioisomers 25b and 26b, as expected on the
basis of stereoelectronic considerations and in agreement with
results of the oxidation of the same substrates with metal
oxides.22 However, the ratios observed in oxidations with IBX
were lower than those obtained with HgO or MnO2.22 Then, use
of IBX does not give advantages in terms of regioselectivity for
the oxidation of unsymmetric hydroxylamines possessing two
methylene groups adjacent to nitrogen. Conversely, hydroxyl-
amines 22−23, possessing a methylene and a methine group at
the α and α′ positions to nitrogen, showed a great and
synthetically significant increase in the nitrone regioisomeric
composition in favor of the aldonitrones 28a and 29a, when the
oxidation was carried out with IBX instead of with MnO2 (entries
5−6). Particularly remarkable was the oxidation of the acyclic
hydroxylamine 21, which yielded the aldonitrone 27a almost
exclusively (entry 4). Ketonitrones are expected to be favored on
thermodynamic grounds, while aldonitrones should be favored
sterically (and statistically). Consequently, we may infer that
regioselectivity in the oxidation of hydroxylamines with IBX is
mostly driven by steric effects.
a
Reaction conditions: hydroxylamine (0.1−1.6 mmol) in 0.09 M dry
b
CH2Cl2, IBX (1.5 equiv), rt, 2 h. Yield of crude product (>98%
c
purity). Determined by integration of 1H NMR spectrum of the crude
reaction mixture; in parentheses the ratios obtained by oxidation with
HgO (entry 2) or MnO2 (entries 3, 5, 6).
Scheme 1. Mechanism Proposed for the IBX Oxidation of
Hydroxylamines
The mildness and rapidity of this reaction led us to anticipate a
chemoselectivity for the oxidation of hydroxylamines compared
to other functional groups susceptible to oxidation by IBX. This
assumption was confirmed by the completely selective oxidation
of hydroxylamine 6 in the presence of 1-hexanol (see Supporting
Information).
Concerning the mechanism of the oxidation of hydroxyl-
amines with IBX, we propose coordination of the IBX iodine
atom at nitrogen, rather than at oxygen, to give adducts 31
(Scheme 1). Spectroscopic evidence substantiating this hypoth-
esis was collected. Indeed, 1H NMR of the oxidation mixture of
hydroxylamine 6 recorded at an early stage showed the splitting
of the quartet of the methylene H’s α to nitrogen into two
multiplets, in agreement with transformation of two equivalent H
atoms (A2X3 system) into two diastereotopic ones (ABX3
system) consequent to quaternization of nitrogen (see
Supporting Information). Then, the initial stage is similar to
that proposed by Nicolaou and co-workers for the IBX oxidation
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02029.
■
S
Detailed experimental procedures and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
(13) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019−
8022.
*E-mail: andrea.goti@unifi.it.
Notes
(14) Duschek, A.; Kirsch, F. Angew. Chem., Int. Ed. 2011, 50, 1524−
1552.
The authors declare no competing financial interest.
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Chem., Int. Ed. 2003, 42, 4077−4082. (b) Nicolaou, K. C.; Mathison, C.
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ACKNOWLEDGMENTS
We thank MIUR-Italy (PRIN 2010−2011, 2010L9SH3K 006)
■
and Universita
̀
degli Studi di Firenze (Fondi Ateneo) for financial
support. We are grateful to Dr. Francesca Liguori for the
preparation of hydroxylamine 13 and its oxidation with different
reagents.
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