Solvent-free synthesis of nitrones in a ball-mill

Article abstract of DOI:10.1016/j.tet.2008.03.091

Various C-aryl and C-alkyl-nitrones were synthesized within 0.5-2 h via condensation of an equimolar amount of aldehydes and N-substituted-hydroxylamines under solvent-free conditions in?a ball-mill apparatus. Reactions can be performed without the need of excluding air and moisture and yields the expected products with no need for further purification. The study has been complemented by Differential Scanning Calorimetry (DSC) and solid-state ¹³C MAS nuclear magnetic resonance experiments. We have also studied the temperature profile during the reaction. A comparative study with the corresponding solvent-free microwave activated reaction showed the superiority of the ball-milling method; 31 examples are described, including the synthesis of the anti-aging agent C-phenyl-N-tert-butyl nitrone (PBN) and one of its analogues C-2-pyridyl-N-tert-butylnitrone (2-PyBN).

Full text of DOI:10.1016/j.tet.2008.03.091

Tetrahedron 64 (2008) 5569–5576
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-free synthesis of nitrones in a ball-mill
a
a
b
a
a,
*
´ ´
Evelina Colacino , Pierrick Nun , Francesco Maria Colacino , Jean Martinez , Frederic Lamaty
a Institut des Biomole´cules Max Mousseron, UMR 5247 CNRS-Universite´ Montpellier 1 et Universite´ Montpellier 2, Place Euge`ne Bataillon, 34095 Montpellier cedex 05, France
b Department of Experimental and Clinical Medicine, University of Magna Graecia 88100 Germaneto, Catanzaro, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Various C-aryl and C-alkyl-nitrones were synthesized within 0.5–2 h via condensation of an equimolar
amount of aldehydes and N-substituted-hydroxylamines under solvent-free conditions in a ball-mill
apparatus. Reactions can be performed without the need of excluding air and moisture and yields the
expected products with no need for further purification. The study has been complemented by Differ-
ential Scanning Calorimetry (DSC) and solid-state 13C MAS nuclear magnetic resonance experiments. We
have also studied the temperature profile during the reaction. A comparative study with the corre-
sponding solvent-free microwave activated reaction showed the superiority of the ball-milling method;
31 examples are described, including the synthesis of the anti-aging agent C-phenyl-N-tert-butyl nitrone
(PBN) and one of its analogues C-2-pyridyl-N-tert-butylnitrone (2-PyBN).
Received 19 February 2008
Received in revised form 18 March 2008
Accepted 26 March 2008
Available online 1 April 2008
Keywords:
Waste prevention
Solid-state reactions
Mechanochemical activation
Nitrones
Ó 2008 Elsevier Ltd. All rights reserved.
Solvent-free reactions
1. Introduction
and the radical thus becomes inactivated and unable to interfere in
biochemical processes and damage cellular tissues.
Ball-milling is a mechanochemical technique that is widely
applied to the grinding of minerals into fine particles and to the
preparation and modification of inorganic solids.1,2 Ball-mill
chemistry is of interest because it takes place under mild conditions,
in the absence of solvent, and in environmentally friendly condi-
tions. In the last years, this technique has found interest in synthetic
organic chemistry.3,4 The reported examples include functionaliza-
tion of fullerenes,5 reductive benzylation of malonitrile,6 protection
of amines,7 Knoevenagel reaction,8 aldol condensation9 and its
asymmetric version,10 Michael additions,8 preparation of phos-
phorus ylides,11 oxidative coupling of 2-naphthol,12 and Heck-type
cross-coupling reactions.13,14
We report herein the application of this non-conventional meth-
odology for the preparation of different nitrones, which are highly
valuable synthetic intermediates in organic synthesis. They behave as
electrophiles toward organometallics and as 1,3-dipoles in cycload-
ditions.15 Recently, novel reactivities have been described.16–18
Nitrones have relevant applications as spin traps in biological
studies,19 and are efficient in age-related diseases,20 due to both in
vitro and in vivo21 stability of resulting nitroxide radicals. The
nitrone compound reacts with a free radical to form a derivative
called spin adduct. Once the adduct is formed, it is relatively stable
The most common procedures for the preparation of nitrones
consist in condensation of aldehydes with N-monosubstituted
hydroxylamines,22–25 or oxidation of secondary amines or N,N-
disubstituted hydroxylamine.15,26 Even though good to excellent
results could be achieved in both cases, they present still some
limitations, including the use of organic solvents, relatively long
reaction times, use of an excess of the aldehyde to achieve high
conversion, and tedious chromatographic purifications. Moreover,
only a few of these procedures employed environmentally benign
oxidants with metal catalysts.27–30 In order to find a more efficient
and benign methodology31 for the synthesis of nitrones, we in-
vestigated solvent-free ball-mill chemistry, which is a ‘highlight of
green chemistry’.
2. Results and discussion
We chose as a model the stoichiometric reaction between
benzaldehyde 1a (0.5 mmol) and N-methylhydroxylamine hydro-
chloride 2 (0.5 mmol), in the presence of sodium bicarbonate
(0.5 mmol) (Scheme 1).
The mixture was introduced into a stainless steel jar (10 mL).
The reaction vessel was closed and fixed on the vibration arms of
a ball-milling apparatus, along with two stainless balls of 7.0 mm
diameter (Retsch MM200 mixer mill, Retsch GmbH, Hann, Ger-
many),7 using a second parallel jar to equilibrate the system. Then,
both vessels were vibrated vigorously at a frequency of 30 Hz
at room temperature. To obtain an analytical sample, the crude
* Corresponding author. Tel.: þ33 467143847; fax: þ33 467144866
E-mail address: frederic.lamaty@univ-montp2.fr (F. Lamaty).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.091

5570
E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
O
CH3
Ball Milling
O
N
(solvent free)
+
+
2 H2O
NaCl +
+
CO2
CH3NHOH . HCl
H
30 Hz, 1h
NaHCO3
H
1a
2
3
Scheme 1. Synthesis of N-methyl-C-phenyl nitrone 3.
mixture was recovered by following a straightforward and easy
work-up procedure. A minimum amount of dichloromethane was
added to the crude, filtered on cotton to eliminate NaCl. The filtrate
was evaporated affording the N-methyl-C-phenyl nitrone 3 in 82%
yield. 1H NMR of the mixture detected only the expected product
with total consumption of the starting materials. For practical use,
nitrone can be used without further purification to eliminate NaCl,
alternatively, the product can be recovered by precipitation of the
crude from water, poor solvent for nitrones. It is common to add
some NaCl as an additive to improve the mechanical properties of
the reaction mixture,12 but in our case, it was not needed. It is
important to note that under typical ball-milling conditions, the
mechanical agitation process led to a slight heating of the reaction
vessel, along with a slight pressure inside the vessel that was
detected when opening.
It is worth mentioning that the best results were obtained when
using a 1:1 starting material ratio. The use of an excess of one of the
reagents is detrimental to the conversion of the reaction. During
the synthesis of nitrones, the hydroxylamine function is usually
activated by adding a base such as triethylamine or sodium bi-
carbonate in the mixture. Since dry-milling has proved to be more
efficient, solid sodium bicarbonate was chosen and gave the best
results. We also reacted aldehyde 1e and hydroxylamine hydro-
chloride 2, during 2 h (Table 1), in absence of sodium bicarbonate.
At the end of the experiment, the sticky crude was recovered by
methanol, filtered, and the solvent evaporated. The crude was
analyzed by 1H NMR, using CH2Br2 as an internal standard. The
reaction was incomplete (the conversion of aldehyde 1e was 77%)
and the 1H NMR yield of nitrone 12 was 59%. When we performed
the reactions at a lower frequency (10 Hz or 20 Hz) for a period of
time between 30 min and 2 h, the aldehyde and hydroxylamine
were still present in the crude, probably due to diminished amount
of energy per impact. Ball-milling with pause resulted in lower
conversion. Ball-milling experiments were again more suitable for
a scale-up procedure and from a practical point of view. The stoi-
chiometric reaction between aldehyde 1b (5.0 mmol) and N-
methylhydroxylamine hydrochloride 2 (5.0 mmol) in the presence
of sodium bicarbonate (5.0 mmol) after 30 min showed the for-
mation of nitrone 8 in 88% yield. Unfortunately, when we run the
same experiment on 10.0 mmol scale, the lower substrate conver-
sion (68%) is a result of an inefficient mixing, showing that the
10 ml jar was not adapted for such a scale. The milled material was
qualitatively finer than the original starting materials and it accu-
mulated on both the top and the bottom of jar. A compact layer is
formed, constituted by nitrone 8 and unreacted starting materials.
This avoids the impact energy from the grinding ball to be more
effectively applied on the residual sample.
We also investigated the synthesis of nitrone 8 by Differential
Scanning Calorimetry (DSC), running four independent experi-
ments. First, 4-cyanobenzaldehyde 1b, N-methylhydroxylamine
hydrochloride 2, and preceding synthesized nitrone 8 according to
our methodology, were separately analyzed by DSC (warm-up rate:
10 ꢀC/min), and their respective melting points confirmed by
thermograms. Then, we heated-up a mixture of 1b, 2, and the base
for 2 h, from 24 ꢀC to 250 ꢀC (warm-up rate 2 ꢀC/min) without
stirring. This resulted in a decomposition of all the starting mate-
rials, without formation of nitrone 8, as demonstrated after 1H NMR
analysis of the crude, showing the necessity of the shaking move-
ment. From the model studies, it is apparent that it is not sufficient
to simply heat the reaction mixture in a vessel. Apparently, the ball-
milling created conditions that are difficult to obtain under usual
conditions. It is most probably the combination of pressure, heat,
grinding, and stirring that provides the conditions necessary for the
successful outcome of the reaction.1,3,7
The effect of three milling operating conditions has been in-
vestigated through the variation of external temperature of the
vessel measured during the milling experiment for a period of
30 min at 30 Hz: (a) empty vessel; (b) reaction on 0.5 mmol scale;
and (c) reaction on 5.0 mmol scale. For ambient milling, the starting
temperature of the sample is in all cases at approximately 30 ꢀC and
rises to nearly 44 ꢀC (experiment a) or 40 ꢀC (experiments b and c)
at the end of the test.32 Through a heat transfer lumped parameter
mathematical model,32 describing the milling apparatus, starting
from its mechano-physical properties, we were able to determine
that the temperature experimented inside the jar is the same as the
external one.
We extended the methodology to other arylaldehydes 1b–h in
the presence of N-methyl-, N-benzyl-, and N-tert-butylhydroxyl-
amine hydrochlorides (2, 4, and 5, respectively). The results are
summarized in Table 1 (Scheme 2).
Table 1
Synthesis of nitrones 3 and 6–16 by condensation of various arylaldehydes 1a–h
In all cases the reaction proceeded as a one-step condensation to
give the corresponding nitrones 6–16 in nearly quantitative yields,
without the need to exclude air and moisture, in a shorter reaction
time than by classical methods, but with comparable yields, where
excess of reagents under inert atmosphere are reacted at room
temperature or under heating for 1 or 2 days.15,26
with R2NHOH$HCl 2, 4, and 5
R1
R2NHOH$HCl
T (h)
Product
Yield (%)
ball-milla
Yield (%)
microwaveb
C6H5
C6H5
C6H5
1a
1a
1a
1b
1b
1c
1d
1e
1f
2
4
5
2
4
2
2
2
2
2
4
2
1
1
2
0.5
2
0.5
1
1
2
0.5
2
3
6
82
88
100
93
99
94
100
94
100
96
88
91
72
80
74
64
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
65
7 (PBN)
8
9
10
11
12
13
14
15
When the yields are inferior to 100%, this is due to incomplete
recovery of the nitrone/NaCl mixture from the ball-mill jar. In all
4-CN–C6H4
4-CN–C6H4
4-NO2–C6H4
4-I–C6H4
3-I–C6H4
2-I–C6H4
4-CH3–C6H4
4-CH3–C6H4
3-CH3–C6H4
R2
H
Ball Milling
O
O
N
(solvent free)
R2NHOH . HCl
+
R1
H
R1
1g
1g
1h
30 Hz
NaHCO3
2
16
n.d.
1a-r
2 R2 = CH3
4 R2 = Bn
5 R2 = C(CH3)3
6-31
a
Yields of isolated pure nitrones. All reactions reached complete conversion,
unless otherwise stated.
b
Comparative experiment under microwave activation 3 h at 120 ꢀC (optimized
conditions).
Scheme 2.

E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
5571
the cases discussed herein, full conversion to the expected product
was obtained. This was further demonstrated by cross polarization/
magic angle spinning (CP/MAS) 13C NMR analysis of the reaction
mixture, arising from the reaction of aldehyde 1e with N-methyl-
hydroxylamine hydrochloride 2, in the presence of base, directly
without any treatment with a solvent. Figure 1 shows three CP/MAS
13C spectra. The first two correspond to the starting materials. The
third one shows complete disappearance of the peaks corre-
sponding to the starting materials and it displays resonances only
for the expected nitrone 12. N-tert-Butyl-a-phenyl nitrone (PBN) 7
was obtained in quantitative yield in mild conditions without ob-
serving any undesired oxidation of the hydroxylamine to nitroso
compound, as previously described, during its synthesis under 24 h
reflux conditions in dichloromethane.24 PBN is one of the most
studied, since it inhibits oxidation of lipoproteins,33 it displays
neuroprotective activity,34 and exhibits potent antisenescent ef-
fects most notably in neurodegenerative diseases such as Parkin-
son’s, Alzheimer’s disease, and Stroke syndrome.21 The reaction
proved to be general with respect to the nature of the substituent or
to its position on the aromatic ring. Comparative condensation
experiments were also carried out between aldehydes 1b and 1e,f
using N-methylhydroxylamine hydrochloride as-received from
commercial suppliers without further purification, or after a double
recrystallization from an AcOEt/EtOH mixture.
In all cases, higher yields of nitrones were obtained using
recrystallized hydroxylamine 2, and total conversion of the starting
materials.
To confirm the advantages of the ball-milling technology,
a comparative study underoptimized conditions, using a microwave
synthesizer under solvent-free conditions, was undertaken.18,35,36
Theyields of nitrones 3, 6–8, and 15 dropped drasticallycompared to
the corresponding ball-milling experiments. The reactions pro-
ceeded more slowly (up to 2 h), at high temperature (120 ꢀC) and
without achieving a total conversion of the starting aldehydes 1a,
1b, and 1g, maybe due to a degradation of the free hydroxylamine
and to a slurry of NaHCO3 in melts, which provokes a lower yield.
High yields of nitrones 3 and 6 (up to 95%) could only be obtained in
dichloromethane solution, using an excess of hydroxylamine 2
(2.5 equiv) under microwave irradiation.35 Purification by column
chromatography was then necessary to recover the products.
To further prove the general concept, the methodology was
extended to other heteroaromatic or aliphatic aldehydes. Results
are summarized in Table 2. Heteroaromatic aldehydes such as
2-furfural 1l, 2-thiophenylcarbaldehyde 1m, and pyr-
idinecarbaldehydes 1i–k were also excellent substrates. This
method gave straightforward access to biologically important
nitrones. For example, furylnitrone 23 was obtained in good yield,
being reported that furylnitrones reduce infarct volume in an in
vivo model.37 An analogue of the widely used spin trap N-tert-
butyl-a-nitrone 7 (PBN), N-tert-butyl-a-(2-pyridyl)nitrone 22 (2-
PyBN), known to show enhanced complexation properties38 of
metal due to its chelating pyridyl group, was obtained in good
yields. Alkylaldonitrones 30 and 31, known to be thermoin-
stables,39 were also easily obtained in high yields too and charac-
terized. Unfortunately, if n-butyraldehyde 1q is reacted in the
Table 2
Synthesis of heteroaromatic and aliphatic nitrones 17–32 by condensation of alde-
hydes 1i–r with R2NHOH$HCl 2, 4, and 5
R1
R2NHOH$HCl
T (h)
Product
Yielda (%)
4-C5H4N–
4-C5H4N–
4-C5H4N–
3-C5H4N–
2-C5H4N–
2-C5H4N–
2-Furyl–
2-Furyl–
2-Thiophenyl–
2-Benzofuranyl–
2-Naphthyl–
2-Naphthyl–
3-Quinolyl–
n-CH3(CH2)2–
n-CH3(CH2)5–
1i
1i
1i
1j
1k
1k
1l
2
4
5
2
2
5
2
4
2
2
2
4
2
2
2
2
2
2
2
2
2
1.5
2
2
0.5
2
2
2
1
17
18
19
20
96
100
98
87
96
71
80
94
92
100
92
100
95
93
90
21
22 (2-PyBN)
23
24
25
26
27
28
29
30
31
1l
1m
1n
1o
1o
1p
1q
1r
1
a
Figure 1. 13C CP/MAS spectra of (a) N-methylhydroxylamine hydrochloride 2; (b) 3-
iodobezaldehyde 1e, and (c) (Z)-N-(3-iodobenzylidene)methylamine N-oxide 12.
Yields of isolated pure nitrones. All reactions reached complete conversion
unless otherwise stated.

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E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
presence of N-benzylhydroxylamine hydrochloride 4, (instead of N-
hydroxylamine hydrochloride 2) the conversion of starting mate-
rials was quantitative, but the corresponding nitrone proved to be
very unstable. Moreover, during the solution condensation re-
action, the yield of nitrones are known to decrease in the case of
bulky N-tert-butylnitrones compared to N-methylnitrones. Thanks
to the ball-milling technique, electronic effects or steric constraints
on the aldehydes or on the hydroxylamines became negligible, the
corresponding nitrones were obtained in high yields. With the
exception of alkylaldonitrones 30 and 31, which decompose after
few days, all the nitrones proved to be stable after storage at room
temperature up to 1 month and more than 6 months if stored at
ꢁ18 ꢀC. An aqueous solution of pure nitrone 8 showed no de-
composition after 5 days at room temperature. Moreover, a CDCl3
solution of a pure sample of several nitrones (prepared in-
dependently) remained unchanged for weeks without equilibra-
tion to regioisomeric nitrones.40
Ball-milling conditions are undoubtedly very different from
conventional conditions. Therefore we could not assume that the
E,Z-isomeric ratio would be the same as that observed in experi-
ments ran under conventional conditions. By a comparison of
literature spectral data, we concluded that the products obtained
in ball-milling conditions were identical to those already reported
in literature: all the nitrones were in the more stable Z-form,41 with
the exception of N-(napht-2-ylmethylidene)methylamine N-oxide
27, known to be in the E-form.42
(4.5 mg) from 24 ꢀC to 250 ꢀC at a rate of 10 ꢀC/min, or a mixture of
aldehyde 1b (7.5 mg, 0.05 mmol), hydroxylamine hydrochloride 2
(4.2 mg, 0.05 mmol), and NaHCO3 (4.2 mg, 0.05 mmol) from 24 ꢀC to
250 ꢀC at a rate of 2 ꢀC/min. Mass spectra (electrospray ionization
mode, ESIMS) were recorded on a Platform II (Micromass, Man-
chester, UK) quadrupole mass spectrometer fitted with an electro-
spray interface. The mass spectrometer was calibrated in the
positive- and negative-ion ESI mode. The samples were dissolved in
H2O/CH3CN (50/50 v/v). FAB mass spectra and HRMS (High Resolu-
tion Mass Spectrum) were recorded on a JEOL JMS DX300-SX 102 in
positive mode using NBA (3-nitrobenzylalcool) or GT (mixture of
glycerol/thioglycerol 50/50 v/v) as matrix. Infrared spectra were
recorded by diffuse reflectance or by transmittance in KBr salt plates
on a Nicolet Avatar 330FT-IR. Data are reported according to their
group absorption regions as s¼strong, m¼medium, and w¼weak.
Melting points were measured on a Bu¨chi Melting Point 510 appa-
ratus and are uncorrected. Microwave-assisted reactions were per-
formed in sealed vessels witha Biotage Initiator 60 EXPÒ instrument.
The temperature was measured with an IR sensor on the outer
surface of the reaction vial. The Ball-milling experiments were
performed in a Retsch MM200 mixer mill (Retsch GmbH, Hann,
Germany) with two stainless ball of 7.0 mm diameter, into a stainless
jar (10 mL) at a rate of 1800 rounds per minute (30 Hz) at room
temperature. The final temperature in the reaction vessel (40 ꢀC)
was measured with a digital thermometer. All the nitrones 3 and 6–
31 have been obtained as pure compounds and have been identified
by comparison of their spectral and physical data with those
reported in the literature. Analytical high performance liquid chro-
matography (HPLC) was performed on a Waters Millenium 717
equipped with Autosampler, with a variable wavelength diode de-
tector using a CHROMOLITH RP18 column (50ꢂ4,6 mm), flow 5 mL/
min, linear gradient CH3CN in water 0–100% (þ0.1% TFA) in 4.5 min.
3. Conclusion
In summary, nitrones were synthesized for the first time in
a ball-mill under mechanochemical and solvent-free conditions.
This protocol is promising and thus constitutes an appealing al-
ternative both in academic research and in practical processes,
being simple to perform, cheap, scalable, occurring under mild
conditions, and providing only water, NaCl, and CO2 as byproducts.
The methodology is highly profitable in terms of sustainable syn-
thesis with utmost efficiency in all respect, affording products in
pure form without further purification and in high yield. The pro-
tocol described allowed the easy synthesis of nitrones, considered
as good candidates for the treatment of various diseases or as useful
building-blocks for the synthesis of more elaborated structures.
4.2. General experimental procedure for the synthesis
of nitrones 3 and 6–31 (Tables 1 and 2)
4.2.1. Method A: ball-milling conditions
A mixture of aldehyde (0.5 mmol, 1 equiv), N-substituted hy-
droxylamine hydrochloride (0.5 mmol, 1.0 equiv), and NaHCO3
(0.5 mmol, 1.0 equiv) were ball-milled at 30 Hz for 0.5–2
h
(depending on the aldehyde, see Tables 1 and 2). When the reaction
was complete, the reaction mixture was solubilized in CH2Cl2 and
filtered on cotton to eliminate NaCl. The filtrate was evaporated
under vacuum to afford nitrones 3 and 6–31 with high purity. The
yields are tabulated on Tables 1 and 2.
4. Experimental section
4.1. General information
All reagents were purchased from Aldrich Chemical Co. and used
without further purification. Commercial N-methylhydroxylamine
hydrochloride 2 was crystallized twice from a mixture of AcOEt/
EtOH at ꢁ20 ꢀC. 1H and 13C NMR analyses were performed with
Bruker Avance DPX 200 MHz, Bruker Avance AM 300 MHz or Bruker
AC-400 MHz and are reported in parts per million and calibrated
using residual undeuterated solvents as an internal reference. Data
are reported as: br¼broad, s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet; coupling constant(s) in hertz, integration.
Solid-state 13C NMR spectra were recorded on a Bruker Avance AM
operating at 300 MHz with a 4 mm rotor size CP/MAS (cross polar-
ization/magic angle spinning) probe. Measurements of phase-tran-
sition temperatures (Differential Scanning Calorimetry, DSC) were
performed with a Netzsch differential scanning calorimeter, model
204 F1 Phoenix, and the data were evaluated using Netzsch Proteus
Thermal Analysis software version 4.8.1. Samples of 4–16 mg were
placed in a hermetically sealed aluminum pan; an empty pan was
used as a reference. Pans were exposed to a N2 flow atmosphere.
Measurements were performed by heating separately aldehyde 1b
(6.6 mg), hydroxylamine hydrochloride 2 (5.3 mg), and nitrone 8
4.2.2. Method B: microwave conditions (only for nitrones
3, 6–8, and 15)
A mixture of aldehyde (0.5 mmol, 1 equiv), N-substituted hy-
droxylamine (0.5 mmol, 1.0 equiv), and NaHCO3 (0.5 mmol,
1.0 equiv) were heated by microwave irradiation at 120 ꢀC (initial
power 400 W) in three runs of 1 h each. Temperature of 120 ꢀC was
reached in less than 1 min. After cooling, the reaction mixture was
solubilized in CH2Cl2 and filtered on cotton to eliminate NaCl. The
filtrate was evaporated under vacuum to afford the corresponding
nitrones. The yields are tabulated in Table 1 and were calculated by
1H NMR using CH2Br2 (30 mL, 0.43 mmol) as an internal standard.
4.2.3. (Z)-N-Benzylidenemethylamine N-oxide (3) (Table 1,
entry 1)43,44
Method A. The condensation reaction between benzaldehyde 1a
and N-methylhydroxylamine hydrochloride 2 afforded 56 mg of 3
as a yellow solid in 82% yield. Mp 78–81 ꢀC (lit.45 82–83 ꢀC); 1H
NMR (CDCl3) d 8.30–8.20 (m, 2H), 7.37–7.40 (m, 3H), 7.35 (s, CH]N,
1H), 3.87 (s, 3H); 13C NMR (CDCl3) d 135.30,130.49,128.49, 54.44; IR
(KBr): 3416.3 (br), 3062.4 (w), 1596.7 (m), 1445.4 (w), 1165.5 (vs),

E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
5573
943.1 (vs), 846.1 (w), 756.4 (m), 693.6 (s) cmꢁ1; ESIMS m/z 136.1
[MþH]þ; FAB(þ) m/z 136.1 [MþH]þ; HRMS Calcd for C8H10NO
[MþH]þ: 136.0762. Found 136.0769.
a dark yellow solid in 94% yield. Mp 212–214 ꢀC (lit.53 217–218 ꢀC);
1H NMR (CDCl3) d 8.41 (d, J¼9.0 Hz, 2H), 8.29 (d, J¼9.0 Hz, 2H), 7.58
(s, CH]N, 1H), 3.98 (s, 3H); 13C NMR (CDCl3) d 147.22, 135.40,
132.57, 128.46, 123.72, 54.55; IR (KBr): 3425.0 (w), 3112.8 (w),
1598.1 (m), 1510.7 (s), 1341.33 (s), 1185.18 (m), 1165.7 (m), 1110.9
(m), 947.8 (m), 867.7 (m), 687.8 (w) cmꢁ1; ESIMS m/z 181.1 [MþH]þ;
FAB(þ) m/z 181.1 [MþH]þ; HRMS Calcd for C8H9N2O3 [MþH]þ:
181.0613. Found 181.0608.
Method B. Yellow solid in 72% yield.
4.2.4. (Z)-N-Benzylidenebenzylamine N-oxide (6) (Table 1,
entry 2)43,44
Method A. The condensation reaction between benzaldehyde 1a
and N-benzylhydroxylamine hydrochloride 4 afforded 93 mg of 6
as a white solid in 88% yield. Mp 78–80 ꢀC (lit.46 81–83 ꢀC); 1H NMR
(CDCl3) d 8.32–8.19 (m, 2H), 7.37–7.51 (m, 8H), 7.31 (s, CH]N, 1H),
5.08 (s, 2H); 13C NMR (CDCl3) d 134.48, 130.31, 130.40, 129.23,
128.97, 128.69, 128.47, 71.22; IR (KBr): 3184.0 (br), 3064.1 (w),
3031.4, 2816.5 (w), 1582.8 (m), 1565.8, 1493.8 (w), 1457.6 (s), 1424.3
(m), 1320.8 (m), 1299.5 (w), 1147.0 (vs), 939.8 (vs), 815.9 (w), 756.4
(m), 817.8 (m), 754.2 (m), 703.6 (s), 690.8 (s) cmꢁ1; ESIMS m/z 212.1
[MþH]þ; FAB(þ) m/z 212.1 [MþH]þ; HRMS Calcd for C14H13NO
[MþH]þ: 212.1075. Found 212.1068.
4.2.9. (Z)-N-(4-Iodobenzylidene)methylamine N-oxide (11)
(Table 1, entry 7)
Method A. The condensation reaction between aldehyde 1d and
N-methylhydroxylamine hydrochloride 2 afforded 131 mg of 11 as
a pale yellow solid in 100% yield. Mp 143–147 ꢀC; 1H NMR (CDCl3)
d 8.01 (d, J¼8.6 Hz, 2H), 7.81 (d, J¼8.6 Hz, 2H), 7.33 (s, CH]N, 1H),
3.87 (s, 3H); 13C NMR (CDCl3) d 137.72, 134.23, 129.83, 129.67, 96.37,
54.63; IR (KBr): 3444.1 (w), 3073.9 (w), 1590.4 (m), 1573.29 (m),
1403.0 (w), 1182.9 (s), 1167.9 (s), 946.9 (m), 831.1 (s), 678.9 (w)
cmꢁ1; ESIMS m/z 262.0 [MþH]þ; FAB(þ) m/z 262.0 [MþH]þ; HRMS
Calcd for C8H9INO [MþH]þ: 261.9729. Found 261.9736.
Method B. White solid in 80% yield.
4.2.5. (Z)-N-Benzylidene-tert-butylamine N-oxide (7)
(Table 1, entry 3)47–49
4.2.10. (Z)-N-(3-Iodobenzylidene)methylamine N-oxide (12)
(Table 1, entry 8)
Method A. The condensation reaction between benzaldehyde 1a
and N-tert-butylhydroxylamine hydrochloride 5 afforded 88 mg of
7 as a pale brown solid in 100% yield. Mp 71–72 ꢀC (lit.50 75–76 ꢀC);
1H NMR (CDCl3) d 8.38–8.22 (m, 2H), 7.58 (s, CH]N, 1H), 7.42–7.38
(m, 3H), 1.58 (s, C(CH3)3, 9H); 13C NMR (CDCl3) d 131.02, 130.09,
129.86, 128.77, 128.40, 70.78, 28.31; IR (KBr): 3421.04 (br), 2935.58
(w), 1579.0 (s), 1562.6 (m), 1444.4 (m), 1415.6 (m), 1364.8 (s), 1193.3
(w), 1118.6 (s), 1076.66 (w), 905.0 (w), 835.9 (w), 757.7 (m), 696.0
(m) cmꢁ1; ESIMS m/z 178.1 [MþH]þ, 122.2 [MꢁC(CH3)3]þ; FAB(þ)
m/z 178.1 [MþH]þ; HRMS Calcd for C11H16NO [MþH]þ: 178.1232.
Found 178.1217.
Method A. The condensation reaction between aldehyde 1e and
N-methylhydroxylamine hydrochloride 2 afforded 124 mg of 12 as
a white solid in 94% yield. Mp 93–95 ꢀC; 1H NMR (CDCl3) d 8.63 (s,
1H), 8.18 (d, J¼7.9 Hz, 1H), 7.75 (d, J¼7.9 Hz, 1H), 7.32 (s, CH]N, 1H),
7.18 (t, J¼7.9 Hz, 1H); 13C NMR (CDCl3) d 139.45, 136.58, 133.61,
130.1, 127.39, 94.22, 54.66; IR (KBr): 3430.8 (br), 3077.4 (w), 1575.1
(w), 1384.2 (s), 1173.8 (m), 1161.7 (w), 948.2 (m), 807.9 (s), 688.8 (w)
cmꢁ1; ESIMS m/z 261.9.0 [MþH]þ; FAB(þ) m/z 262.0 [MþH]þ;
HRMS Calcd for C8H9INO [MþH]þ: 261.9729. Found 261.9732.
Method B. Pale brown solid in 74% yield.
4.2.11. (Z)-N-(2-Iodobenzylidene)methylamine N-oxide (13)
(Table 1, entry 9)
4.2.6. (Z)-N-(4-Cyanobenzylidene)methylamine N-oxide (8)
(Table 1, entry 4)24
Method A. The condensation reaction between aldehyde 1f and
N-methylhydroxylamine hydrochloride 2 afforded 131 mg of 13 as
a white solid in 100% yield. Mp 116–118 ꢀC; 1H NMR (CDCl3) d 9.23
(d, J¼7.5 Hz, 1H), 7.95 (d, J¼7.5 Hz, 1H), 7.78 (s, CH]N, 1H), 7.45 (t,
J¼7.5 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H); 13C NMR (CDCl3) d 139.70,
138.57, 132.30, 131.59, 129.18, 128.47, 98.97, 55.22; IR (KBr): 3432.4
(br), 3085.6 (w), 1574.1 (w), 1406.2 (w), 1166.3 (s), 946.9 (m), 748.9
(m) cmꢁ1; ESIMS m/z 261.9.0 [MþH]þ, 135.2 [(MꢁI)þH]þ; FAB(þ)
m/z 262.0 [MþH]þ; HRMS Calcd for C8H9INO [MþH]þ: 261.9729.
Found 261.9729.
Method A. The condensation reaction between aldehyde 1b and
N-methylhydroxylamine hydrochloride 2 afforded 74 mg of 8 as
a white solid in 93% yield. Mp 184–186 ꢀC (lit.45 187 ꢀC); 1H NMR
(CDCl3) d 8.24 (d, J¼8.5 Hz, 2H), 7.64 (d, J¼8.5 Hz, 2H), 7.40 (s,
CH]N, 1H), 3.91 (s, 3H); 13C NMR (CDCl3) d 134.28, 133.47, 132.80,
132.25, 128.30, 118.51, 113.03, 55.03; IR (KBr): 3416.2 (w), 2996.2
(w), 2223.3 (s), 1585.6.0 (s), 1548.7 (s), 1442.5 (m), 1421.6 (m),
1185.6 (s), 1167.1 (s), 1095.3 (w), 947.2 (s), 852.4 (s), 590.7 (s), 544.1
(s) cmꢁ1; ESIMS m/z 161.1 [MþH]þ; FAB(þ) m/z 161.1 [MþH]þ;
HRMS Calcd for C9H9N2O [MþH]þ: 161.0715. Found 161.0713.
Method B. White solid in 64% yield.
4.2.12. (Z)-N-(4-Methylbenzylidene)methylamine N-oxide (14)
(Table 1, entry 10)24,52,54
Method A. The condensation reaction between aldehyde 1g and
N-methylhydroxylamine hydrochloride 2 afforded 72 mg of 14 as
a white solid in 96% yield. Mp 118–120 ꢀC (lit.25 119–121 ꢀC); 1H
NMR (CDCl3) d 8.18 (d, J¼7.2 Hz, 2H), 7.43 (s, CH]N, 1H), 7.21 (d,
J¼7.2 Hz, 2H), 3.83 (s, 3H), 2.42 (s, NCH3, 3H); 13C NMR (CDCl3)
d 140.87,135.27,129.70,128.94,127.82, 54.19, 21.65; IR (KBr): 3438.8
(br), 3086.1 (w),1586.3 (w),1414.7 (s),1163.2 (s), 944.2 (s), 839.6 (s),
588.4 (m), 501.9 (s) cmꢁ1; ESIMS m/z 200.0 [2MþH]þ, 150.1
[MþH]þ; FAB(þ) m/z 150.1 [MþH]þ; HRMS Calcd for C9H12NO
[MþH]þ: 150.0919. Found 150.0911.
4.2.7. (Z)-N-(4-Cyanobenzylidene)benzylamine N-oxide (9)
(Table 1, entry 5)51
Method A. The condensation reaction between aldehyde 1b and
N-benzylhydroxylamine hydrochloride 4 afforded 117 mg of 9 as
a pale yellow solid in 99% yield. Mp 140–142 ꢀC (lit.51 143–150 ꢀC);
1H NMR (CDCl3) d 8.32 (d, J¼8.6 Hz, 2H), 7.71 (d, J¼8.6 Hz, 2H),
7.55–7.40 (m, 6H), 5.09 (s, 2H); 13C NMR (CDCl3) d 134.32, 132.77,
132.58, 132.16, 129.30, 129.08, 128.50, 128.05, 118.59, 112.85, 71.87;
IR (KBr): 3065.3 (w), 2224.4 (s), 1573.4 (s), 1542.9 (w), 1448.3 (m),
1149.4 (s), 937.4 (m), 861.8 (s), 698.1 (s), 564.8 (m) cmꢁ1; ESIMS m/z
237.0 [MþH]þ; FAB(þ) m/z 237.1 [MþH]þ; HRMS Calcd for
4.2.13. (Z)-N-(4-Methylbenzylidene)benzylamine N-oxide (15)
(Table 1, entry 11)55
C
15H13N2O [MþH]þ: 237.1028. Found 237.1030.
Method A. The condensation reaction between aldehyde 1g and
N-benzylhydroxylamine hydrochloride 4 afforded 99 mg of 15 as
a white solid in 88% yield. Mp 116–118 ꢀC; 1H NMR (CDCl3) d 8.15 (d,
J¼7.7 Hz, 2H), 7.59–7.34 (m, 5H), 7.26 (d, J¼7.7 Hz, 2H), 5.12 (s, 2H),
2.45 (s, NCH3, 3H); 13C NMR (CDCl3) d 140.96,134.38, 133.38,129.22,
4.2.8. (Z)-N-(4-Nitrobenzylidene)methylamine N-oxide (10)
(Table 1, entry 6)24,45,52
Method A. The condensation reaction between aldehyde 1c and
N-methylhydroxylamine hydrochloride 2 afforded 87 mg of 10 as

5574
E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
129.17, 128.95, 128.69, 127.78, 71.01, 21.68; IR (KBr): 3066 (w),
3032.1 (w), 1609.2 (w), 1497.7 (s), 1458.2 (s), 1431.2 (w), 939.2 (s),
849.6 (s), 829.4 (m) cmꢁ1; ESIMS m/z 451.2 [2MþH]þ, 248.1
[MþNa]þ, 226.0 [MþH]þ; FAB(þ) m/z 226.1 [MþH]þ; HRMS Calcd
for C15H16NO [MþH]þ: 226.1232. Found 226.1222.
d 150.59, 149.58, 134.46, 132.28, 126.99, 123.53, 54.59; IR (KBr):
3408.8 (br s), 1649.3 (m), 1588.7 (m), 1483.9 (w), 1414.5 (s), 1192.9
(m), 1168.4 (s), 944.9 (m), 704.1 (s), 536.6 (m) cmꢁ1; ESIMS m/z
137.1 [MþH]þ; FAB(þ) m/z 137.1 [MþH]þ; HRMS Calcd for C7H9N2O
[MþH]þ: 137.0715. Found 137.0707.
Method B. White solid in 65% yield.
4.2.19. (Z)-N-(Pyridine-2-ylmethylidene)methylamine N-oxide (21)
(Table 2, entry 5)39
4.2.14. (Z)-N-(3-Methylbenzylidene)methylamine N-oxide (16)
(Table 1, entry 12)
Method A. The condensation reaction between aldehyde 1k and
N-methylhydroxylamine hydrochloride 2 afforded 65 mg of 21 as
deep orange solid in 96% yield. Mp 48–50 ꢀC (lit.39 48–50 ꢀC); 1H
NMR (CDCl3) d 9.12 (d, J¼8.0 Hz, 1H), 8.62 (d, J¼4.8 Hz, 1H), 7.81 (t,
J¼7.6 Hz, 1H), 7.70 (s, CH]N, 1H), 7.32–7.28 (m, 1H), 3.93 (s, 3H);
13C NMR (CDCl3) d 149.56, 149.42, 136.81, 136.62, 124.33, 123.60,
54.81; IR (KBr): 3409.6 (br s), 1658.8 (m), 1587.4 (m), 1567.7 (m),
1437.9 (m),1409.1 (s), 1167.3 (s), 1145.5 (s), 950.0 (s), 774.6 (s), 545.6
(m) cmꢁ1; ESIMS m/z 159.1 [MþNa]þ, 137.1 [MþH]þ; FAB(þ) m/z
137.1 [MþH]þ; HRMS Calcd for C7H9N2O [MþH]þ: 137.0715. Found
137.0717.
Method A. The condensation reaction between aldehyde 1h and
N-methylhydroxylamine hydrochloride 2 afforded 68 mg of 16 as
deep orange oil in 91% yield. 1H NMR (CDCl3) d 8.13 (s, 1H), 7.97 (d,
J¼7.6 Hz, 1H), 7.38 (m, 2H), 7.28 (m, 2H), 3.95 (s, NCH3, 3H), 2.45 (s,
3H); 13C NMR (CDCl3) d 138.12, 135.55, 131.37, 130.33, 128.88,
128.35, 127.18, 125.78, 54.32, 21.41; IR (KBr): 3404.7 (br), 2929.1
(m), 1653.11 (w), 1597.6 (m), 1413.7 (s), 1173.4 (s), 1159.8 (s), 946.4
(m), 909.5 (w), 786.8 (m), 693.2 (s) cmꢁ1; ESIMS m/z 299.2
[2MþH]þ, 172.2 [MþNa]þ, 150.1 [MþH]þ; FAB(þ) m/z 150.1
[MþH]þ; HRMS Calcd for C9H12NO [MþH]þ: 150.0919. Found
150.0929.
4.2.20. (Z)-N-(Pyridine-2-ylmethylidene)-tert-butylamine N-oxide
(22) (Table 2, entry 6)49
4.2.15. (Z)-N-(Pyridine-4-ylmethylidene)methylamine N-oxide (17)
(Table 2, entry 1)
Method A. The condensation reaction between aldehyde 1k and
N-tert-butylhydroxylamine hydrochloride 5 afforded 63 mg of 22 as
white needles in 71% yield. Mp 63–65 ꢀC (lit.49 62–63 ꢀC); 1H NMR
(CDCl3) d 9.25 (d, J¼8.1 Hz, 1H), 8.62 (d, J¼4.8 Hz, 1H), 7.92 (s,
CH]N, 1H), 7.81 (dt, J¼1.7 Hz and 7.8 Hz, 1H), 7.32 (m, 1H), 1.65 (s,
9H); 13C NMR (CDCl3) d 150.13, 149.37, 136.84, 131.55, 124.02,
123.56, 71.65, 28.47, 28.23, 27.96; IR (KBr): 3428.5 (br s), 2980.4 (m),
1560.4 (m), 1437.5 (m), 1407.1 (s), 1198.1 (s), 1122.5 (s), 913.0 (s),
Method A. The condensation reaction between aldehyde 1i and
N-methylhydroxylamine hydrochloride 2 afforded 65 mg of 17 as
deep yellow solid in 96% yield. Mp 106–108 ꢀC; 1H NMR (CDCl3)
d 8.65 (br s, 2H), 8.05 (d, J¼5.5 Hz, 2H), 7.45 (s, CH]N, 1H), 3.95
(s, NCH3, 3H); 13C NMR (CDCl3) d 150.41, 136.76, 133.14, 121.25,
55.11; IR (KBr): 3412.6 (br), 1648.2 (w), 1594.3 (s), 1414.2 (s), 1173.3
(s), 948.1 (m), 847.7 (m), 534.7 (m) cmꢁ1; ESIMS m/z 137.1 [MþH]þ;
FAB(þ) m/z 137.1 [MþH]þ; HRMS Calcd for C7H9N2O [MþH]þ:
137.0715. Found 137.0695.
816.4 (s), 744.6 (s) cmꢁ1
;
ESIMS m/z 179.2 [MþH]þ, 123.2
[(MꢁC(CH3)3)þH]þ; FAB(þ) m/z 179.1 [MþH]þ; HRMS Calcd for
C
10H15N2O [MþH]þ: 179.1184. Found 179.1201.
4.2.16. (Z)-N-(Pyridine-4-ylmethylidene)benzylamine N-oxide (18)
(Table 2, entry 2)
4.2.21. (Z)-N-(Fur-2-ylmethylidene)methylamine N-oxide (23)
(Table 2, entry 7)39,43
MethodA. The condensationreactionbetweenaldehyde 1iand N-
benzylhydroxylamine hydrochloride 4 afforded 106 mg of 18 as
deep brown solid in 100% yield. Mp 103–105 ꢀC; 1H NMR (CDCl3)
d 8.78 (br s, 2H), 8.05 (br s, 2H), 7.45 (br s, 6H), 5.15 (s, 2H); 13C NMR
(CDCl3) d 150.26, 136.71, 132.59, 132.22, 129.28, 129.15, 129.07,
128.94, 128.58, 128.45, 126.75, 121.58, 72.00; IR (KBr): 3422.8 (w),
3052.5 (w),1561.2 (m),1459.1 (m),1430.9 (m),1155.3 (m),1205.3 (s),
1155.3 (s), 863.8 (s), 769.9 (m), 719.9 (s), 573.6 (m), 517.7 (m), 497.1
(m) cmꢁ1; ESIMS m/z 213.2 [MþH]þ; FAB(þ) m/z 213.1 [MþH]þ;
HRMS Calcd for C13H13N2O [MþH]þ: 213.1028. Found 213.1046.
Method A. The condensation reaction between aldehyde 1l and
N-methylhydroxylamine hydrochloride 2 afforded 50 mg of 23 as
a white solid in 80% yield. Mp 79–81 ꢀC (lit.59 91–92 ꢀC); 1H NMR
(CDCl3) d 7.75 (d, J¼3.4 Hz, 1H), 7.53 (s, CH]N, 1H), 7.47 (br s, 1H),
6.55 (dd, J¼3.3 Hz and 1.7 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3)
d 146.70,143.61,126.23,115.24,112.29, 52.76; IR (KBr): 3390.7 (br s),
3156.4 (m), 3110.6 (m), 1666.4 (w), 1620.1 (m), 1607.7 (m), 1561.53
(w), 1481.45 (m), 1411.9 (m), 1400.3(m), 1231.1 (s), 1141.8 (s), 1010.9
(s), 939.7 (s), 825.7 (m), 767.6 (s), 593.3 (m), 555.2 (m) cmꢁ1; ESIMS
m/z 126.0 [MþH]þ; FAB(þ) m/z 126.1 [MþH]þ; HRMS Calcd for
C6H8NO2 [MþH]þ: 126.0555. Found 126.0563.
4.2.17. (Z)-N-(Pyridine-4-ylmethylidene)-tert-butylamine N-oxide
(19) (Table 2, entry 3)49,57
Method A. The condensation reaction between aldehyde 1i and
N-tert-butylhydroxylamine hydrochloride 5 afforded 87 mg of 19 as
deep orange solid in 98% yield. Mp 84–86 ꢀC (lit.57 99–101 ꢀC); 1H
NMR (CDCl3) d 8.89 (br s, 2H), 8.18 (br s, 2H), 7.58 (s, CH]N, 1H),
1.58 (s, 9H); 13C NMR (CDCl3) d 149.20, 137.12, 128.17, 123.46, 72.32,
53.49, 28.45, 28.20, 27.95; IR (KBr): 3422.1 (w), 2977.7 (w), 1587.9
(s), 141.6 (s), 1363.6 (m), 1188.7 (m), 1136.0 (s), 988.8 (m), 836.6 (s),
544.1 (m), 529.6 (m) cmꢁ1; ESIMS m/z 179.0 [MþH]þ, 123.2
[(MꢁC(CH3)3)þH]þ; FAB(þ) m/z 179.1 [MþH]þ; HRMS Calcd for
4.2.22. (Z)-N-(Fur-2-ylmethylidene)benzylamine N-oxide (24)
(Table 2, entry 8)60
Method A. The condensation reaction between aldehyde 1l and
N-benzylhydroxylamine hydrochloride 4 afforded 94 mg of 24 as
a light brown solid in 94% yield. Mp 85–88 ꢀC (lit.60 88 ꢀC); 1H NMR
(CDCl3) d 7.79 (br s, 1H), 7.65–7.32 (br s, 7H), 7.62 (br s, 1H), 5.06 (s,
2H); 13C NMR (CDCl3) d 146.83, 143.72, 132.84, 129.41, 129.04,
128.44, 125.24, 115.37, 112.34, 69.57; IR (KBr): 3442.6 (br w), 3191.0
(w), 3066.4 (w), 1582.5 (m), 1558.1 (m), 1485.4 (s), 1438.4 (m),
1427.83 (m),1137.06 (s), 1008.6 (m), 930.2 (m), 916.7 (m), 814.2 (m),
737.5 (s), 703.4 (s), 671.8 (m), 593.2 (m), 559.3 (m) cmꢁ1; ESIMS m/z
224.1 [MþNa]þ, 202.2 [MþH]þ; FAB(þ) m/z 202.1 [MþH]þ; HRMS
Calcd for C12H12NO2 [MþH]þ: 202.0868. Found 202.0861.
C
10H15N2O [MþH]þ: 179.1184. Found 179.1187.
4.2.18. (Z)-N-(Pyridine-3-ylmethylidene)methylamine N-oxide (20)
(Table 2, entry 4)58
Method A. The condensation reaction between aldehyde 1j and
N-methylhydroxylamine hydrochloride 2 afforded 59 mg of 20 as
deep violet solid in 87% yield. Mp 74–76 ꢀC (lit.58 74–76 ꢀC); 1H
NMR (CDCl3) d 8.95 (m, 2H), 8.56 (d, 1H), 7.43 (s, CH]N, 1H), 7.35
(dd, J¼4.8 Hz and J¼7.9 Hz, 1H), 3.93 (s, 3H); 13C NMR (CDCl3)
4.2.23. (Z)-N-(Thiophen-2-ylmethylidene)methylamine N-oxide
(25) (Table 2, entry 9)
Method A. The condensation reaction between aldehyde 1m and
N-methylhydroxylamine hydrochloride 2 afforded 65 mg of 25 as

E. Colacino et al. / Tetrahedron 64 (2008) 5569–5576
5575
a white solid in 92% yield. Mp 115–117 ꢀC; 1H NMR (CDCl3) d 7.89 (s,
1H), 7.50 (br d, 1H), 7.45 (br d, 1H), 7.17 (dd, J¼3.8 Hz, J¼5.0 Hz, 1H),
3.92 (s, 3H); 13C NMR (CDCl3) d 132.41, 130.82, 129.25, 128.99,
126.47, 51.71; IR (KBr): 3425.1 (br s), 3064.0 (w), 2967.64 (w),
1585.4 (s), 1389.7 (s), 1253.6 (m), 1228.8 (m), 1162.4 (s), 1092.9 (w),
1044.8 (m), 952.9 (s), 855.4 (s), 763.6 (s), 702.9 (s), 599.8 (m), 537.3
(m) cmꢁ1; ESIMS m/z 142.1 [MþH]þ; FAB(þ) m/z 142.0 [MþH]þ;
HRMS Calcd for C6H8NOS [MþH]þ: 142.0327. Found 142.0314.
(m), 1666.6 (s), 1601.9 (m), 1572.0 (m), 1498.5 (m), 1420.9 (s), 1348.1
(s), 1195.9 (w), 1158.9 (s), 949.0 (m), 921.8 (s), 862.2 (w), 782.9 (s),
754.3 (s), 649.1 (m), 637.6 (m), 468.9 (m) cmꢁ1; ESIMS m/z 187.1
[MþH]þ; FAB(þ) m/z 187.1 [MþH]þ; HRMS Calcd for C11H11N2O
[MþH]þ: 187.0871. Found 187.0872.
4.2.28. (Z)-N-(n-Butylidene)methylamine N-oxide (30)
(Table 2, entry 14)
Method A. The condensation reaction between aldehyde 1q and
N-methylhydroxylamine hydrochloride 2 afforded 47 mg of 30 as
a colorless oil in 93% yield. 1H NMR (CDCl3) d 6.71 (t, J¼5.8 Hz, 1H),
3.71 (s, 3H), 2.51 (br q, J¼7.4 Hz and 1.3 Hz, 2H), 1.58 (septet,
J¼7.5 Hz, 2H), 0.99 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3) d 140.63,
52.32, 28.73, 18.89, 13.93; IR (KBr): 3399.4 (br s), 2963.7 (s), 2875.4
(s), 1660.6 (s), 1459.1 (s), 1386.9 (m),1080.3 (w), 947.2 (w), 627.1 (w)
cmꢁ1; ESIMS m/z 203.2 [Mþ2H]þ, 102.0 [MþH]þ; FAB(þ) m/z 102.1
[MþH]þ; HRMS Calcd for C5H12NO [MþH]þ: 102.0910. Found
102.0922.
4.2.24. (Z)-N-(Benzofuran-2-ylmethylidene)methylamine N-oxide
(26) (Table 2, entry 10)
Method A. The condensation reaction between aldehyde 1n and
N-methylhydroxylamine hydrochloride 2 afforded 87 mg of 26 as
a pale yellow solid in 100% yield. Mp 108–110 ꢀC; 1H NMR (CDCl3)
d 8.18 (br s, 1H), 7.71–7.67 (m, 1H), 7.51–7.45 (m, 1H), 7.41 (dd,
J¼6.96 Hz and 1.41 Hz, 1H), 7.33 (dd, J¼4.71 Hz and 1.41 Hz, 1H),
7.28 (dd, J¼6.96 Hz and 1.33 Hz, 1H), 3.92 (s, 3H); 13C NMR (CDCl3)
d 154.40, 147.68, 128.35, 126.54, 126.24, 123.42, 122.44, 111.08,
110.91, 53.44; IR (KBr): 3419.5 (br w), 3141.1 (w), 3028.9 (w), 2947.4
(w), 1593.6 (m), 1543.4 (m), 1450.5 (m), 1409.6 (s), 1392.6 (m),
1343.9 (m), 1266.1 (m), 1247.3 (s), 1203.5 (s), 1134.6 (m), 955.9 (s),
4.2.29. (Z)-N-(n-Heptylidene)methylamine N-oxide (31)
(Table 2, entry 15)43
867.7 (s), 780.1 (s), 753.9 (s), 747.3 (s), 655.0 (m), 518.6 (m) cmꢁ1
;
Method A. The condensation reaction between aldehyde 1r and
N-methylhydroxylamine hydrochloride 2 afforded 64 mg of 31 as
a colorless oil in 90% yield. 1H NMR (CDCl3) d 6.67 (t, J¼5.8 Hz, 1H),
4.71 (s, 3H), 2.45 (br q, J¼6.8 Hz, 2H), 1.55 (m, 2H), 1.50–1.20 (m,
6H), 0.89 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3) d 140.92, 52.31, 31.44,
29.11, 26.85, 25.43, 22.47, 13.98; IR (KBr): 3297.6 (br s), 2927.3 (s),
2860.1 (s), 1668.1 (s), 1461.33 (s), 1378.9 (w), 1102.4 (w), 947.8 (w),
728.48 (w) cmꢁ1; ESIMS m/z 287.2 [Mþ2H]þ, 144.2 [MþH]þ;
FAB(þ) m/z 144.1 [MþH]þ; HRMS Calcd for C8H18NO [MþH]þ:
144.1388. Found 144.1378.
ESIMS m/z 176.1 [MþH]þ; FAB(þ) m/z 176.1 [MþH]þ; HRMS Calcd
for C10H10NO2 [MþH]þ: 176.0712. Found 176.0713.
4.2.25. (E)-N-(Napht-2-ylmethylidene)methylamine N-oxide (27)
(Table 2, entry 11)42
Method A. The condensation reaction between aldehyde 1o and
N-methylhydroxylamine hydrochloride 2 afforded 85 mg of 27 as
a deep yellow solid in 92% yield. Mp 108–110 ꢀC (lit.39 106–108 ꢀC);
1H NMR (CDCl3) d 9.22 (s, CH]N, 1H), 7.95–7.88 (m, 1H), 7.85–7.78
(m, 3H), 7.55–7.45 (m, 3H), 3.92 (s, 3H); 13C NMR (CDCl3) d 162.59,
135.23, 134.12, 133.13, 129.21, 128.42, 127.98, 127.72, 127.55, 127.36,
126.51, 125.66, 54.51; IR (KBr): 3420.6 (br w), 3078.5 (w), 3057.9
(w), 2996.8 (w), 2941.4 (w), 1578.2 (m), 1566.5 (w), 1502.2 (w),
1416.77 (s), 1404.3 (m), 1380.3 (m), 1364.2 (m), 1274.5 (w), 1125.5
(m), 968.8 (m), 957.5 (m), 904.9 (m), 869.9 (s), 841.9 (s), 753.4 (s),
482.7 (s) cmꢁ1; ESIMS m/z 371.1 [Mþ2H]þ, 208.1 [MþNa]þ, 186.2
[MþH]þ; FAB(þ) m/z 186.1 [MþH]þ; HRMS Calcd for C12H12NO
[MþH]þ: 186.0919. Found 186.0918.
Acknowledgements
We thank Dr. Lydie Viau from the Institut Charles Gerhardt
(UMR 5253, CMOS group, Montpellier, France) for DSC experi-
ments, MENRT, CNRS, the Ligue Contre le Cancer and the Fondation
d’Entreprise EADS for financial support.
Supplementary data
4.2.26. (Z)-N-(Napht-2-ylmethylidene)benzylamine N-oxide (28)
(Table 2, entry 12)28,55
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.03.091.
Method A. The condensation reaction between aldehyde 1o and
N-benzylhydroxylamine hydrochloride 4 afforded 131 mg of 28 as
a pale orange solid in 100% yield. Mp 104–106 ꢀC (lit.28 107–
108 ꢀC); 1H NMR (CDCl3) d 9.25 (s, CH]N, 1H), 7.92–7.77 (m, 4H),
7.68–7.32 (m, 8H), 5.11 (s, 2H); 13C NMR (CDCl3) d 134.34, 134.14,
133.40, 133.14, 129.56, 129.26, 129.00, 128.61, 128.32, 127.94, 127.73,
127.56, 127.39, 126.54, 125.95, 71.28; IR (KBr): 3441.5 (br w), 3056.8
(w), 3028.9 (w), 1572.4 (m), 1497.1 (w), 1451.5 (m), 1353.9 (m),
1229.9 (m), 1183.6 (m), 1161.3 (m), 1142.2 (m), 945.5 (m), 901.6 (m),
866.6 (s), 829.9 (m), 732.2 (s), 701.4 (s), 479.3 (s) cmꢁ1; ESIMS m/z
523.0 [Mþ2H]þ, 262.1 [MþH]þ; FAB(þ) m/z 262.1 [MþH]þ; HRMS
Calcd for C18H16NO [MþH]þ: 262.1232. Found 262.1234.
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