Gold Supported on Silica Catalyzes the Aerobic Oxidation of N,N-Disubstituted Hydroxylamines to Nitrones

Article abstract of DOI:10.1002/ejoc.201501001

A new method for the preparation of nitrones through the aerobic oxidation of the corresponding N,N-disubstituted hydroxylamines has been developed by exploring a new catalytic reactivity of gold supported on silica. The oxidation occurs under very mild c

Full text of DOI:10.1002/ejoc.201501001

FULL PAPER
DOI: 10.1002/ejoc.201501001
Gold Supported on Silica Catalyzes the Aerobic Oxidation of N,N-
Disubstituted Hydroxylamines to Nitrones
Giampiero D’Adamio,[a] Camilla Parmeggiani,[a,b] Andrea Goti,[a] and Francesca Cardona*[a]
Keywords: Nitrones / Hydroxylamines / Gold / Nanoparticles / Oxidation / Supported catalysts
A new method for the preparation of nitrones through the
aerobic oxidation of the corresponding N,N-disubstituted
hydroxylamines has been developed by exploring a new
catalytic reactivity of gold supported on silica. The oxidation
occurs under very mild conditions (flux of air, methanol or
water, room temperature). The oxidation of a range of highly
functionalized hydroxylamines with complete conversions
and excellent yields of nitrones illustrates the selectivity, effi-
ciency, and reliability of this practical method. The oxidation
was shown to take place chemoselectively in competition ex-
periments with benzyl alcohol and dibutylamine.
Nitrones can be synthesized by intramolecular condensa-
Introduction
tion reactions,[6a] N-alkylation of oximes,[6a,8] metal-medi-
Oxygen and air are ideal oxidants from an environmental ated ring-expansion reactions,[9] or oxidation reactions
point of view,[1] since they are safe and inexpensive, and (starting from isoxazolidines,[10] imines,[11] N,N-disubsti-
produce only water as a coproduct. In particular, the aero- tuted amines,[12] or hydroxylamines[6a]). We have been inter-
bic oxidation of alcohols is a very important reaction; the ested in this topic for a number of years, and in particular,
development of new catalysts and more practical and regarding the oxidation of hydroxylamines 1 to nitrones 2
greener methods to achieve this reaction is a very active (Scheme 1), we have proposed some procedures using either
research topic. The use of a transition-metal catalyst in stoichiometric oxidants (e.g., NaOCl,[13] MnO2[14]) or metal
combination with oxygen for the oxidation of alcohols to catalysts [e.g., methyltrioxorhenium (MTO)[15] or tetra-
the corresponding carbonyl compounds represents an propylammonium perruthenate (TPAP)[16]] in combination
emerging sustainable alternative to traditional proce- with hydrogen peroxide or N-methylmorpholine N-oxide
dures.[2–4] Both homogeneous and heterogeneous catalytic (NMO).
systems have been developed,[2,3] and more recently, cataly-
sis by metals in the form of nanoparticles has been intro-
duced.[3,4]
The related oxidation of N,N-disubstituted hydroxyl-
amines to nitrones has been studied much less, despite the
Scheme 1. Oxidative dehydrogenation of N,N-disubstituted hydrox-
ylamines to give nitrones.
growing importance of these latter compounds as spin traps
in biological studies, and as drugs for age-related diseases.[5]
Moreover, nitrones are key intermediates for the total syn-
In our preliminary efforts to replace such oxidants with
thesis of nitrogen-containing natural products and other a greener one (e.g., oxygen), a TPAP catalyst gave some
biologically active compounds. In this regard, they can re- positive results.[17] However, the procedure was sluggish,
act not only as electrophiles with organometallic reagents, and suffered from low reproducibility. Moreover, an unde-
or as 1,3-dipoles in [3+2] cycloaddition reactions,[6] but also sirable solvent such as dichloromethane was required, along
as substrates for [3+3] cycloadditions, or as reagents in new with a 5 mol-% catalyst loading and molecular sieves. The
metal-mediated reactions.[7]
isolated yields of the products were moderate, especially
with more complex and highly functionalized nitrones, due
to the difficulties encountered in removing the homogen-
eous catalyst by flash column chromatography.
Although elemental gold has long been thought to be
inert as a catalyst, it has recently been recognized that gold
nanoparticles are surprisingly active catalysts for aerobic
oxidation[18] and other reactions,[19] resulting in a popular
research topic at the frontier between homogeneous and
heterogeneous catalysis. In particular, the aerobic oxidation
[a] Dipartimento di Chimica “Ugo Schiff”,
University of Florence,
via della Lastruccia 3-13, 50019 Sesto F.no, Italy
E-mail: francesca.cardona@unifi.it
http://www.chimica.unifi.it/
[b] Istituto Nazionale di Ottica at LENS,
Consiglio Nazionale delle Ricerche,
via Nello Carrara 1, 50019 Sesto F.no, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501001.
Eur. J. Org. Chem. 2015, 6541–6546
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6541

G. D’Adamio, C. Parmeggiani, A. Goti, F. Cardona
FULL PAPER
of alcohols by gold catalysts in the gas and liquid phases is Table 1. Aerobic oxidation of N,N-dibenzylhydroxylamine by gold
well documented.[20]
on silica.
Recently, a few reports on the ability of elemental gold
powder and gold nanoparticles to catalyze the aerobic oxid-
ation of nitrogen-containing compounds that are tradition-
ally known for their poisoning effect on metal catalysts,
such as primary and secondary amines (to nitriles, alde-
Entry Cat. [mol-%] Solvent
Temp. Time [h] Conv. [%][a]
hydes, amides, or imines), have appeared in the literature.[21]
Based on these reports, and intrigued by the observations
that hydroxylamine is oxidized by gold electrodes[22] and
that it has also been used as seeding agent to produce gold
nanowires by the use of gold nanoparticle structures as tem-
plate,[23] we envisaged that nanogold catalysts may be able
to perform the oxidative dehydrogenation of N,N-disubsti-
tuted hydroxylamines to give the corresponding nitrones in
the presence of oxygen (or even better, air) as stoichiometric
oxidant.
In this paper, we report our results on the unprecedented
reactivity of a known heterogeneous gold catalyst in the
presence of a simple flush of air as the oxidant. We chose
the gold catalyst supported on silica previously reported
and completely characterized by Biella and Rossi,[24] which
showed a new reactivity towards hydroxylamines for their
efficient and practical conversion into nitrones.
1
2
0
0
MeOH
MeOH
r.t.
reflux
reflux
r.t.
50 °C
reflux
r.t.
48
0.5
2
48
1
0.5
16
48
48
72
72
40
30
48
16
0
0
31
100
100
100
100[b]
0
3
4
5
6
7
8
9
10
11
12
13
14
15
2.5
5.0
5.0
5.0
8.0
8.0
8.0
8.0
8.0
5.0
5.0
8.0[c]
8.0[d]
MeOH
MeOH
MeOH
MeOH
MeOH
acetone
EtOAc
EtOH
MeOH/iPrOH, 5:1
H2O/MeOH, 5:1
H2O
MeOH
MeOH
r.t.
r.t.
0
r.t.
33
r.t.
r.t.
100
63
50 °C
r.t.
100
0
r.t.
100
1
[a] Determined by H NMR spectroscopy. [b] A 98% yield of the
nitrone was obtained after flash column chromatography. [c] Re-
used after simple filtration. [d] Reused after reactivation with “pira-
nha” solution (see text).
creased the reaction time necessary for complete conversion
to 1 h or 30 min, respectively (Table 1, Entries 5 and 6). A
further increase in the amount of catalyst to 8 mol-% re-
Results and Discussion
N,N-Dibenzylhydroxylamine (1a) was selected as a model sulted in complete conversion at room temperature within
substrate (0.19 mmol) to study its oxidation to nitrone 2a. 16 h (Table 1, Entry 7). The 1H NMR spectrum of the
The Biella and Rossi catalyst, originally proposed for the crude mixture was very clean, and showed no trace of other
gas-phase oxidation of alcohols,[24] was chosen for the sim- products; after flash column chromatography, the pure
plicity of its preparation; an aqueous solution of tetra- nitrone was isolated in 98% yield. The reaction appeared
chloroauric acid is treated with NH3 and NaBH4 as the to be strongly solvent-dependent. Other halide-free solvents
reducing agent for nanoparticle formation. XRPD (X-ray were investigated (acetone, EtOH, EtOAc; Table 1, En-
powder diffraction) characterization of the resulting cata- tries 8–10), but acetone and EtOAc completely suppressed
lyst confirmed the presence of metallic gold (2θ = 38.3°). the reaction, and a conversion of only 33% was observed
The mean diameter of the gold particles ranged from 10 to in EtOH at room temperature after 3 d (Table 1, Entry 10).
23 nm, in good agreement with previously reported re- A 5:1 mixture of MeOH/iPrOH gave a 100% conversion
sults.[24] The results obtained in the oxidation reaction using after 3 d (Table 1, Entry 11). A suspension of 1a in a quite
a flux of air in different solvents, at different temperatures, dilute 5:1 H2O/MeOH mixture (0.01 m) was stirred at room
and with different amounts of the catalyst are reported in temperature for 40 h, and a good 63% conversion was
Table 1.
reached (Table 1, Entry 12). Finally, by heating hydroxyl-
MeOH was investigated first, due to the good solubility amine 1a at 50 °C in a 0.01 m solution in water for 30 h, the
of hydroxylamine 1a in this solvent. Unfortunately, water solubility problems of 1a in this solvent were overcome, and
(in principle the ideal solvent)[25] was initially discounted complete conversion was observed (Table 1, Entry 13).
since 1a is insoluble in this solvent, and moreover, nitrones Interestingly, hydrolysis of the nitrone did not occur in this
may undergo catalytic hydrolytic cleavage to aldehydes and case.
hydroxylamines in aqueous solvents. Two control experi-
To improve the efficiency of the catalyst, we tested
ments were carried out in the absence of catalyst; no con- whether it could be recycled or reused for the oxidation of
version was seen either at room temperature or with heating further batches of substrate. Simple filtration of the catalyst
at reflux temperature (Table 1, Entries 1–2). To our delight, and reuse in a second run was effective only for longer reac-
a promising 31% conversion of the starting material was tion times (no conversion at room temperature after 48 h;
observed upon heating for 2 h in the presence of 2.5 mol-% Table 1, Entry 14; ca. 100% conversion at room tempera-
of the catalyst (Table 1, Entry 3). The use of 5 mol-% of Au/ ture after 1 week). The third run was even less effective
SiO2 resulted in the complete conversion of 1a into 2a at (20% conversion at room temperature after 1 week). This
room temperature within 2 d (Table 1, Entry 4). Increasing might be ascribed to passivation of the catalyst surface as
the reaction temperature to 50 °C or reflux temperature de- a result of handling. The XRPD spectrum of the catalyst
6542
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6541–6546

Aerobic Oxidation of N,N-Disubstituted Hydroxylamines
Table 2. Aerobic oxidation of N,N-disubstituted hydroxylamines with Au/SiO2 (5 mol-%).[a]
[a] Reaction conditions: substrate (0.19 mmol), Au/SiO2 (5 mol-%), solvent, air. [b] Determined by 1H NMR spectroscopy. [c] Determined
1
by H NMR spectroscopy. [d] Combined isolated yield after flash column chromatography. [e] After 24 h at room temperature in MeOH,
only 58% conversion of the hydroxylamine was observed. [f] 10 mol-% catalyst was used.
Eur. J. Org. Chem. 2015, 6541–6546
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6543

G. D’Adamio, C. Parmeggiani, A. Goti, F. Cardona
FULL PAPER
recovered after a 48 h reaction at room temperature was heating in MeOH. 3-O-TIPS-protected hydroxypyrrolidine
identical to the spectrum of the freshly prepared catalyst; a 1g (TIPS = triisopropylsilyl) was transformed into nitrone
slight change in the mean diameter of the gold particles has 2Ag and 2Bg in a 2:1 ratio (Table 2, Entry 9).
previously been reported for reactions carried out at 300 °C
In all other cases, an almost equimolar mixture of the
for 18 h.[24] To reactivate the catalyst, we used a known aldonitrone and the ketonitrone was formed, with a slight
method based on the filtration of the catalyst and treatment preference for ketonitrones 2Bh–2Bj (Table 2, Entries 10–
with the so-called “piranha” solution [a 3:1 mixture of 13). The regioselectivity did not seem to be solvent-depend-
H2SO4/H2O2 (30% aq.)].[21a,26] This gave a renewed catalyst ent, since oxidation of carbohydrate-derived hydroxylamine
that showed the same performance as the fresh one 1h in MeOH or H2O gave approximately the same re-
(Table 1, Entry 15). Alternatively, after having performed gioisomeric ratios of the two nitrones (i.e., 2Ah and 2Bh;
the oxidation as reported in Table 1, Entry 4, addition of a Table 2, Entries 10 and 11).
further equal amount of 1a to the reaction mixture gave,
Two competition experiments were carried out in
after a further 48 h at room temperature, complete conver- CD3OD (NMR tube) with N,N-dibenzylhydroxylamine (1a)
sion of the hydroxylamine. Therefore, a second run of the in the presence of other compounds that would be suscepti-
reaction takes place with the same efficiency provided that ble, in principle, to oxidation by the gold catalyst, namely
the catalyst is not isolated.
benzyl alcohol (3) and dibutylamine (4) (Scheme 2). These
Having identified the best reaction conditions for the experiments allowed us to simply verify by analysis of the
1
complete conversion of substrate 1a, we addressed the sub- signals of the H NMR spectra the high chemoselectivity
strate scope of the reaction using 5 mol-% of Au/SiO2 in of the hydroxylamine oxidation. Indeed, when a 1:1 mixture
MeOH or H2O, with a series of both aliphatic and benzylic of dibenzylhydroxylamine (1a) and benzyl alcohol (3) or
hydroxylamines, including cyclic and enantiopure examples dibutylamine (4) was subjected to the oxidation by Au/SiO2
(Table 2; for detailed references and characterization of new (5 mol-%), a 1:1 mixture of benzyl alcohol (3) and nitrone
products, see the Supporting Information). In particular, 2a or dibutylamine (4) and nitrone 2a was detected in the
hydroxylated and carbohydrate-derived hydroxylamines 1g, reaction mixture at room temperature after 48 h, or even
1h, and 1i were chosen as substrates since the corresponding after heating at 50 °C for 48 h, showing that benzyl alcohol
nitrones have been extensively used for the total synthesis (3) and dibutylamine (4) are completely inert under these
of natural products and other biologically active poly- conditions (Scheme 2). Therefore, the reaction was com-
hydroxylated alkaloids.[6h,27] Good to excellent conversions pletely chemoselective in favor of hydroxylamine oxidation
and isolated yields of nitrones were obtained in all cases, vs. alcohol or amine oxidation. These findings are consis-
apart from hydroxylamine 1k, which gave only a 9% con- tent with the harsher conditions used in the reported oxid-
version after prolonged reaction times at 50 °C (Table 2, ation of alcohols with the same catalyst.[24]
Entry 10). In this single case, the reaction did not work, and
the only hypothesis we can make at this stage is that the
steric hindrance of the isopropylidene protecting groups
hampers the coordination of the substrate to the catalyst,
and therefore inhibits the reaction. When unsymmetrically
disubstituted hydroxylamines were used, two regioisomeric
nitrones were always formed (Table 2, Entries 3 and 9–
13),[28] apart from ketonitrone 2f, which was formed exclu-
sively (Table 2, Entry 8). The oxidation of N-benzyl-N-oc-
tylhydroxylamine (1c) favored the formation of the more
Scheme 2. Competition experiments with benzyl alcohol and dibut-
ylamine.
stable conjugated nitrone (i.e., 2Ac), which was formed to-
gether with isomer 2Bc in a 3:1 ratio (Table 2, Entry 3).
When the same reaction was run in H2O as solvent (Table 2,
Entry 4), only nitrone 2Ac was isolated, albeit in a low 47%
yield. Probably, the less stable regioisomeric nitrone (i.e.,
2Bc) underwent hydrolysis in the aqueous solvent under the
reaction conditions.
To further investigate the regioselectivity issue with other
aliphatic hydroxylamines, the oxidation of hydroxylamine
1d, bearing an additional methyl group, was undertaken in
both MeOH and H2O as solvents. Since little conversion of
the hydroxylamine took place at room temperature in
MeOH, the reaction mixture was heated at 50 °C in MeOH
and H2O (Table 2, Entries 5 and 6); only aldonitrone 2Ad
was isolated, albeit in low yields (36 and 38%, respectively),
which shows that also in these cases hydrolysis of the nitro-
To further confirm that the reported reaction does not
promote the oxidation of aldehydes, alcohols, or amines, the
catalytic system was investigated in the oxidation of benz-
aldehyde, benzyl alcohol, and dibenzylamine. No extensive
oxidation of any of these compounds was observed upon
reaction with Au/SiO2 (5 mol-%) in MeOH at room tem-
perature for 48 h, followed by heating at 50 °C for 72 h;
only the formation of traces of dimethylacetal in the case
of benzaldehyde, and the formation of traces of benzalde-
hyde and its dimethylacetal in the case of benzyl alcohol
were observed.
Conclusions
This paper describes a new, efficient, mild, and chemo-
nes may occur in an aqueous solvent or with prolonged selective synthesis of nitrones through the aerobic oxidation
6544
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6541–6546

Aerobic Oxidation of N,N-Disubstituted Hydroxylamines
12; see the Supporting Information for detailed experimental pro-
cedures).
of N,N-disubstituted hydroxylamines catalyzed by hetero-
geneous gold on silica. The procedure is simple and
straightforward, using heterogeneous gold (5 mol-%) sup-
ported on silica as the catalyst, MeOH as solvent, and a
flux of air into the reaction mixture as the oxidant. After
completion of the reaction, in most cases at room tempera-
ture, the catalyst was filtered off and reused after cleaning
with an oxidizing acidic H2O2 solution, and the nitrones
were recovered by simple evaporation of the solvent and
purification, when necessary. Complete conversions and ex-
cellent yields of nitrones were observed with a range of acy-
clic and cyclic hydroxylamines, including highly function-
Catalyst Recovery: After completion of the reaction, the catalyst
was recovered by filtration through a Büchner funnel. The collected
catalyst was then treated with a freshly prepared “piranha” solution
[3:1 mixture of concentrated H2SO4/H2O2 (30% aq.); 4 mL] as re-
ported.[26b]
Acknowledgments
We thank the Ministero dell’Università e della Ricerca (MIUR),
Italy (PRIN 2010–2011, 2010L9SH3K 006) and the Ministero della
alized carbohydrate-derived compounds. The reactions Salute, Regione Toscana (Ricerca Finalizzata, RF-2011-02347694)
for financial support. We thank Dr. Annalisa Guerri and Dr. Laura
Chelazzi for XRPD measurements.
could also be carried out in H2O as solvent without any
change in the regioselectivity of the nitrone products. How-
ever, this solvent promoted hydrolysis of the products in
some cases.
Work is underway in our laboratories to expand the
scope of this oxidation system to other nitrogen-containing
compounds. Moreover, we are currently investigating the
possibility of making the reaction greener, for example by
preparing the catalyst in situ without additional reducing
agents.
[1] R. A. Sheldon, Chem. Soc. Rev. 2012, 41, 1437–1451.
[2] a) R. A. Sheldon, I. W. C. E. Arends, G.-J. ten Brink, A. Dijk-
sman, Acc. Chem. Res. 2002, 35, 774–781; b) T. Mallat, A.
Baiker, Chem. Rev. 2004, 104, 3037–3058; c) I. E. Markò, P. R.
Giles, M. Tsukazaki, I. Chellé-Regnaut, A. Gautier, R. Du-
meunier, F. Philippart, K. Doda, J.-L. Mutonkole, S. M.
Brown, C. J. Urch, Adv. Inorg. Chem. 2004, 56, 211–240; d)
S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400–3420; Angew.
Chem. 2004, 116, 3480–3501; e) M. J. Schultz, M. S. Sigman,
Tetrahedron 2006, 62, 8227–8241; f) M. S. Sigman, D. R. Jen-
sen, Acc. Chem. Res. 2006, 39, 221–229; g) T. Matsumoto, M.
Ueno, N. Wang, S. Kobayashi, Chem. Asian J. 2008, 3, 196–
214; h) B. Karimi, A. Zamani, J. Iran. Chem. Soc. 2008, 5, S1–
S20; i) K. M. Gligorich, M. S. Sigman, Chem. Commun. 2009,
3854–3867; j) C. P. Vinod, K. Wilson, A. F. Lee, J. Chem. Tech-
nol. Biotechnol. 2011, 86, 161–171.
[3] F. Cardona C. Parmeggiani (Eds.), Transition Metal Catalysis
in Aerobic Alcohol Oxidation, RSC Green Chemistry Book
Series, Cambridge, UK, 2015.
[4] a) A. T. Bell, Science 2003, 299, 1688–1691; b) R. Schlögl,
S. B. A. Hamid, Angew. Chem. Int. Ed. 2004, 43, 1628–1637;
Angew. Chem. 2004, 116, 1656–1667; c) D. Astruc, F. Lu, J. R.
Aranzaes, Angew. Chem. Int. Ed. 2005, 44, 7852–7872; Angew.
Chem. 2005, 117, 8062–8083; d) V. Polshettiwar, R. Varma,
Green Chem. 2010, 12, 743–754; e) S. E. Davis, M. S. Ide, R. J.
Davis, Green Chem. 2013, 15, 17–45.
[5] a) A. Dhainaut, A. Tizot, E. Raimbaud, B. Lockhart, P. Lest-
age, S. Goldstein, J. Med. Chem. 2000, 43, 2165–2175; b) S.
Kotamraju, E. A. Konorev, J. Joseph, B. Kalyanaraman, J.
Biol. Chem. 2000, 275, 33585–33592; c) A. Keszler, B. Kalyana-
raman, N. Hogg, Free Radical Biol. Med. 2003, 35, 1149–1157;
d) R. A. Floyd, Aging Cell 2006, 5, 51–57; e) R. A. Floyd,
R. D. Kopke, C.-H. Choi, S. B. Foster, S. Doblas, R. A.
Towner, Free Radical Biol. Med. 2008, 45, 1361–1374; f) R. A.
Floyd, H. K. Chandru, T. He, R. Towner, Anti-Cancer Agents
Med. Chem. 2011, 11, 373–379; g) R. A. Floyd, H. C. Cas-
tro Faria Neto, G. A. Zimmerman, K. Hensley, R. A. Towner,
Free Radical Biol. Med. 2013, 62, 145–156.
Experimental Section
General Methods: Commercially sourced reagents were used as re-
ceived. All reactions were carried out with magnetic stirring, and
were monitored by TLC on 0.25 mm silica gel plates (Merck F254).
Column chromatography was carried out on silica gel 60 (32–
63 μm) or on silica gel (230–400 mesh, Merck). Yields refer to spec-
troscopically and analytically pure compounds unless otherwise
stated. 1H NMR spectra were recorded with a Varian Mercury-400
or a Varian INOVA 400 instrument at 25 °C. 13C NMR spectra
were recorded with a Varian Gemini-200 instrument. Chemical
shifts were calibrated using tetramethylsilane (1H: δ = 0.00 ppm)
and CDCl3 (13C: δ = 77.0 ppm). Integrals are consistent with as-
signments, and coupling constants are given in Hz. For detailed
peak assignments, 2D spectra were measured (COSY, HSQC,
NOESY, and NOE if necessary). IR spectra were recorded with a
BX FTIR Perkin–Elmer System spectrophotometer. ESI-MS data
were recorded with a Thermo Scientific™ LCQ fleet ion-trap mass
spectrometer. Elemental analyses were carried out with a Perkin–
Elmer 2400 analyzer. Optical rotation measurements were carried
out with a JASCO DIP-370 polarimeter. XRPD analysis was car-
ried out with a Bruker D8 Advance diffractometer equipped with
a Cu X-ray tube and an X-ray LynxEye XE detector.
Preparation of Gold Catalyst: The gold catalyst was prepared as
reported in ref.[24]
[6] Reviews: a) P. Merino, Sci. Synth. 2004, 27, 511–580; b) P. Me-
rino, S. Franco, F. L. Merchan, T. Tejero, Synlett 2000, 442–
454; c) M. Lombardo, C. Trombini, Synthesis 2000, 759–774;
d) J. J. Tufariello, in: 1,3-Dipolar Cycloaddition Chemistry, vol.
2 (Ed.: A. Padwa), John Wiley & Sons, New York, 1984, pp.
83–168; e) M. Frederickson, Tetrahedron 1997, 53, 403–425; f)
K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863–909;
g) R. C. F. Jones, J. N. Martin, in: The Chemistry of Heterocy-
clic Compounds, vol. 59, Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Prod-
ucts (Eds.: A. Padwa, W. H. Pearson), John Wiley & Sons, New
York, 2002, pp. 1–81; h) A. Brandi, F. Cardona, S. Cicchi,
F. M. Cordero, A. Goti, Chem. Eur. J. 2009, 15, 7808–7821.
General Procedure for the Synthesis of Nitrones 2a–2i: The Au cata-
lyst (ca. 5% Au supported on silica; 200 mg) was added to a solu-
tion of hydroxylamines 1a–1i (0.19 mmol) in methanol or H2O
(2.5 mL), and the mixture was left at the appropriate temperature
(see Table 2) under a flow of air for 2–120 h. The reaction was
monitored by TLC or 1H NMR spectroscopic analysis. Finally, the
catalyst was recovered by filtration through a Büchner funnel, and
the filtrate was concentrated under reduced pressure to give nitro-
nes 2a–2i in 36–100% yield. Where possible, flash column
chromatography was used to obtained pure nitrones, including sep-
arated diastereoisomers (Table 2, Entries 1, 3, 4, 5, 6, 7, 8, 9, and
Eur. J. Org. Chem. 2015, 6541–6546
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6545

G. D’Adamio, C. Parmeggiani, A. Goti, F. Cardona
FULL PAPER
[7]
[20] C. Della Pina, E. Falletta, M. Rossi, in: Transition Metal Catal-
ysis in Aerobic Alcohol Oxidation (Eds.: F. Cardona, C. Par-
meggiani), RSC Green Chemistry Book Series, Cambridge,
UK, 2015, pp. 133–154.
a) G. Masson, S. Py, Y. Vallée, Angew. Chem. Int. Ed. 2002, 41,
1772–1775; Angew. Chem. 2002, 114, 1850–1853; b) I. S.
Young, M. A. Kerr, Angew. Chem. Int. Ed. 2003, 42, 3023–
3026; Angew. Chem. 2003, 115, 3131–3134.
[21] a) B. Zhou, R. J. Angelici, Chem. Commun. 2007, 2157–2159;
b) J. Gong, T. Yan, C. B. Mullins, Chem. Commun. 2009, 761–
763; c) A. Grirrane, A. Corma, H. Garcia, J. Catal. 2009, 264,
138–144; d) S. K. Klitgaard, K. Egeblad, U. V. Mentzel, A. G.
Popov, T. Jensen, E. Taarning, I. S. Nielsen, C. H. Christensen,
Green Chem. 2008, 10, 419–423; e) L. Aschwanden, T. Mallat,
F. Krumeich, A. Baiker, J. Mol. Catal. A 2009, 309, 57–62; f)
L. Aschwanden, T. Mallat, F. Krumeich, A. Baiker, ChemCat-
Chem 2010, 2, 666–673.
[22] a) A. J. J. Jabaraj, D. R. Martins de Godoi, D. A. Scherson,
ACS Catal. 2012, 2, 911–915; b) P. Kannan, S. A. John, J.
Nanosci. Nanotechnol. 2011, 11, 2142–2150; c) Y. Chen, D. R.
Martin de Godoi, D. Scherson, J. Electrochem. Soc. 2011, 158,
F29–F35.
[23] S. Meltzer, R. Resch, B. E. Koel, M. E. Thompson, A. Madhu-
kar, A. A. G. Requicha, P. Will, Langmuir 2001, 17, 1713–1718.
[24] S. Biella, M. Rossi, Chem. Commun. 2003, 378–379.
[25] M.-O. Simon, C.-J. Li, Chem. Soc. Rev. 2012, 41, 1415–1427.
[26] a) A. C. Ontko, R. J. Angelici, Langmuir 1998, 14, 3071–3078;
b) B. Zhu, R. J. Angelici, J. Am. Chem. Soc. 2006, 128, 14460–
14461; c) M. Lazar, R. J. Angelici, J. Am. Chem. Soc. 2006,
128, 10613–10620.
[27] Selected examples: a) O. Iwamoto, K. Nagasawa, Org. Lett.
2010, 12, 2150–2153; b) R. Shinohara, T. Akimoto, O. Iwam-
oto, T. Hirokawa, M. Yotsu-Yamashita, K. Yamaoka, K. Na-
gasawa, Chem. Eur. J. 2011, 17, 12144–12152; c) Y.-X. Li, Y.
Shimada, K. Sato, A. Kato, W. Zhang, Y.-M. Jia, G. W. J.
Fleet, M. Xiao, C.-Y. Yu, Org. Lett. 2015, 17, 716–719; d) R.
Lahiri, A. Palanivel, S. A. Kulkarni, Y. D. Vankar, J. Org.
Chem. 2014, 79, 10786–10800; e) H. Zhao, A. Kato, K. Sato,
Y.-M. Jia, C.-Y. Yu, J. Org. Chem. 2013, 78, 7896–7902; f) C.
Parmeggiani, F. Cardona, L. Giusti, H.-U. Reissig, A. Goti,
Chem. Eur. J. 2013, 19, 10595–10604; g) D. Martella, F. Car-
dona, C. Parmeggiani, F. Franco, J. A. Tamayo, I. Robina, E.
Moreno-Clavijo, A. J. Moreno-Vargas, A. Goti, Eur. J. Org.
Chem. 2013, 4047–4056; h) P. Gilles, S. Py, Org. Lett. 2012, 14,
1042–1045; i) I. Delso, T. Tejero, A. Goti, P. Merino, J. Org.
Chem. 2011, 76, 4139–4143; j) A. Kato, Z.-L. Zhang, H.-Y.
Wang, Y.-M. Jia, C.-Y. Yu, K. Kinami, Y. Hirokami, Y. Tsuji,
I. Adachi, R. J. Nash, G. W. J. Fleet, J. Koseki, I. Nakagome,
S. Hirono, J. Org. Chem. 2015, 80, 4501–4515.
[8]
[9]
A. Peer, A. Vasella, Helv. Chim. Acta 1999, 82, 1044–1065.
a) E. L. Kui, A. Kanazawa, J.-F. Poisson, S. Py, Org. Lett. 2014,
16, 4484–4487; b) I. Nakamura, M. Okamoto, Y. Sato, M. Ter-
ada, Angew. Chem. Int. Ed. 2012, 51, 10816–10819; Angew.
Chem. 2012, 124, 10974–10977; c) I. Nakamura, Y. Sato, K.
Takeda, M. Terada, Chem. Eur. J. 2014, 20, 10214–10219.
a) N. A. LeBel, L. A. Spurlock, J. Org. Chem. 1964, 29, 1337–
1339; b) N. A. LeBel, M. E. Post, D. Hwang, J. Org. Chem.
1979, 44, 1819–1823; c) J. J. Tufariello, G. B. Mullen, J. J. Teg-
eler, E. J. Trybulski, S. C. Wong, Sk. A. Ali, J. Am. Chem. Soc.
1979, 101, 2435–2442; d) Sk. A. Ali, M. I. M. Wazeer, Tetrahe-
dron 1993, 49, 4339–4354.
a) F. Cardona, M. Bonanni, G. Soldaini, A. Goti, ChemSus-
Chem 2008, 1, 327–332; b) F. A. Davis, N. Theddu, R. Edupu-
ganti, Org. Lett. 2010, 12, 4118–4121. c) G. Soldaini, F. Car-
dona, A. Goti, Org. Lett. 2007, 9, 473–476.
For selected examples, see: a) S.-I. Murahashi, H. Mitsui, T.
Shiota, T. Tsuda, S. Watanabe, J. Org. Chem. 1990, 55, 1736–
1744; b) S.-I. Murahashi, T. Shiota, Y. Imada, Org. Synth.
1991, 70, 265–271; c) E. Marcantoni, M. Petrini, O. Polimanti,
Tetrahedron Lett. 1995, 36, 3561–3562; d) A. Goti, L. Nannelli,
Tetrahedron Lett. 1996, 37, 6025–6028; e) R. W. Murray, K.
Iyanar, J. X. Chen, J. T. Wearing, J. Org. Chem. 1996, 61, 8099–
8102.
[10]
[11]
[12]
[13] S. Cicchi, M. Corsi, A. Goti, J. Org. Chem. 1999, 64, 7243–
7245.
[14] S. Cicchi, M. Marradi, A. Goti, A. Brandi, Tetrahedron Lett.
2001, 42, 6503–6505.
[15] R. Saladino, V. Neri, F. Cardona, A. Goti, Adv. Synth. Catal.
2004, 346, 639–647.
[16] A. Goti, F. De Sarlo, M. Romani, Tetrahedron Lett. 1994, 35,
6571–6574.
[17] F. Cardona, L. Gorini, A. Goti, Lett. Org. Chem. 2006, 3, 118–
120.
[18] Reviews: a) C. Della Pina, E. Falletta, L. Prati, M. Rossi,
Chem. Soc. Rev. 2008, 37, 2077–2095; b) C. Della Pina, E. Fal-
letta, Catal. Sci. Technol. 2011, 1, 1564–1571; c) T. Tsukuda,
H. Tsunoyama, H. Sakurai, Chem. Asian J. 2011, 6, 736–748;
d) C. Della Pina, E. Falletta, M. Rossi, Chem. Soc. Rev. 2012,
41, 350–369; e) Y. Zhang, X. Cui, F. Shi, Y. Deng, Chem. Rev.
2012, 112, 2467–2505.
[19] a) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. Int. Ed.
2006, 45, 7896–7936; Angew. Chem. 2006, 118, 8064–8105; b)
M. Stratakis, H. Garcia, Chem. Rev. 2012, 112, 4469–4506.
[28] The issue of regioselectivity that always arises in the formation
of nitrones by oxidation of unsymmetrically substituted amines
or hydroxylamines can be circumvented by direct oxidation
from imines; see ref.[11a,11c]
Received: July 30, 2015
Published Online: September 2, 2015
6546
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6541–6546