Rapid, efficient, and room temperature synthesis of nitrones in excellent yields over MgO under solvent-free conditions

Article abstract of DOI:10.1002/hc.20527

A large variety of C-aryl and C-alkyl nitrones were synthesized within 0.5-15 min via the condensation of aldehydes with N-(methyl, phenyl, or t-butyl)hydroxylamines over MgO by hand-grinding with an agate mortar. These reactions were investigated under d

Full text of DOI:10.1002/hc.20527

Heteroatom Chemistry
Volume 20, Number 3, 2009
Rapid, Efficient, and Room Temperature
Synthesis of Nitrones in Excellent Yields over
MgO under Solvent-Free Conditions
Hassan Valizadeh and Leila Dinparast
Department of Chemistry, Faculty of Sciences, Azerbaijan University of Tarbiat Moallem,
P.O. Box 53714-161, Tabriz, Iran
Received 15 November 2008; revised 22 January 2009
allowing a high degree of diastereocontrol. In this
ABSTRACT: A large variety of C-aryl and C-alkyl ni-
context, both the [3 + 2] cycloaddition of nitrones
trones were synthesized within 0.5–15 min via the
to alkenes [2,3] and the alkylation of nitrones by
condensation of aldehydes with N-(methyl, phenyl, or
organometallic reagents [4] have been extensively
t-butyl)hydroxylamines over MgO by hand-grinding
studied and have become reliable synthetic proce-
with an agate mortar. These reactions were inves-
dures. One of the most common procedures for the
tigated under different conditions and over different
synthesis of nitrones is the condensation of aldehy-
solid supports including basic alumina, montemoril-
des and ketones with N-monosubstituted hydroxy-
˚
lonite, MgO, and molecular sieves (pore size 3 A). In
lamines [5,6]. However, this method is difficult for
the preparation of nonconjugated cyclic nitrones
and bulky alkyl group containing ketonitrones. An-
other method for the preparation of nitrones is the
oxidation of N,N-disubstituted hydroxylamines [7]
in which yellow mercuric oxide [8] is most com-
monly used as an oxidant. Direct oxidation of sec-
ondary amines was also reported as a useful method
for the preparation of nitrones [9]. Andrade et al.
reported the microwave (MW)-assisted neat proce-
dures for the synthesis of nitrones [10]. The synthesis
of nitrones in a ball mill has been reported in solvent-
free conditions [11]. In continuation of our recent
interest to use ionic liquids (ILs), water or solvent-
less systems as a green reaction medium [12,13], we
report here the preparation of a variety of nitrones
without using MW and conventional heating tech-
nique in solvent-less system over MgO solid support.
For comparison, the procedure was also examined
in several ILs by grinding or under MW irradiation.
the more interesting cases, nitrones were prepared over
MgO without heating and any catalyst. In this pro-
cedure, nitrones were prepared in a very short time,
excellent yields, and good purity without using harm-
ꢀ
C
ful solvents in the workup.
2009 Wiley Periodicals,
Inc. Heteroatom Chem 20:177–181, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20527
INTRODUCTION
Nitrones are highly valuable intermediates in or-
ganic synthesis. They behave as electrophiles to-
ward organometallics and as 1,3-dipoles in cycload-
ditions [1]. Nitrones are reactive 1,3-dipoles of the
allyl class that are also usually generated in situ.
Nitrones have proved to be very useful tools in the
synthesis of structurally complex molecules, usually
Correspondence to: Hassan Valizadeh;e-mail: h-valizadeh@
azaruniv.edu.
Contract grant sponsor: Research Vice Chancellor of Azerbaijan
RESULTS AND DISCUSSION
In a typical procedure, a mixture of N-methyl-
hydroxylamine hydrochloride, benzaldehyde, and
University of Tarbiat Moallem, Tabriz, Iran.
c
ꢀ
2009 Wiley Periodicals, Inc.
177

178 Valizadeh and Dinparast
_
condensation of the reactants over solid supports or
in ILs was carried out under MW irradiation in opti-
mized conditions, and the pertinent results are given
in Table 1. From the results obtained, as shown in
Table 1, it is clear that the reaction over MgO should
be the method of choice for synthesizing nitrones,
since a comparatively higher yield was achieved in a
shorter reaction time.
Me
O
+
O
N
H
Silica gel, K2CO3
Grinding
H
MeNHOH, HCl
+
SCHEME 1
Consequently, we extended the grinding method
over MgO to other aldehydes in the presence of N-
methyl-, N-phenyl-, and N-tert-butylhydroxylamine
hydrochlorides (2a, 2b, and 2c, respectively) to ob-
tain the corresponding nitrones (Scheme 2). The pro-
cedure is simple and straightforward consisting of
the cogrinding of the two components in a mortar.
After the appropriate time, the reaction mixture is
dissolved in CHCl3 and analyzed by TLC. The prod-
ucts were purified by recrystallization from suitable
solvent and characterized by 1H NMR, 13C NMR, in-
frared (IR), and elemental analyses and mass spec-
trometry. Melting points (entries 1, 3–6, and 10–15)
of all the products were compared with those re-
ported in the literature. Aromatic aldehydes, con-
taining electron-withdrawing groups (entries 5 and
10) as well as electron-donating groups (entries 2,
6, 7, 9, 11–13, and 15), reacted smoothly to afford
the corresponding products in excellent yields. In
general, the aromatic aldehydes react faster than
the aliphatic aldehydes (entries 16 and 17). In all
the cases, the reactions were completed within 2.5–
15 min of the reaction time. In the majority of the
entries, the nitrones were formed fast, with final
yields ranging from good to excellent (Table 2). We
conducted these reactions on a 20-mmol scale and
found them they underwent a smooth transforma-
tion to the nitrone derivatives in good yields. Thus,
the present procedure is amenable for scaling up.
K2CO3 adsorbed on the surface of silica gel was
grinded in a mortar for a certain period of time as
required to complete the reaction (Scheme 1). The
elution of the reaction mixture with chloroform fol-
lowed by the evaporation of solvent furnished the
crude product 3a, which was purified by recrystal-
lization. MW irradiation of the mixture, in place of
grinding, leads to a messy product with the forma-
tion of a tarry material. For optimizing the condi-
tions, we used the substrates in different ratios. It
was found that the best results were obtained with
1:1 starting material ratio. Several solid supports
were screened for this typical reaction for complete
conversions as monitored by thin layer chromatog-
raphy (TLC) to afford the desired product (Table 1).
Evidently, MgO was found to be superior in terms
of yield (98%) and reaction time (2.5 min) as com-
pared with other supports (entries 1–4). In another
experiment, equimolar amounts of reactants were
treated in several butylmethylimidazolium (bmim)-
based I−Ls, [bmim]X, with varying anions such as
Cl−, BF4 , and PF−6 at room temperature. The obser-
vation shows that the reaction in ILs was slower than
the reaction by hand grinding of reactants over MgO
(entries 5–7). The reactions in ILs were conducted at
higher temperatures for optimizing the conditions
and no significant improvements were observed in
yields or reaction times. For comparison, the direct
TABLE 1 Effect of Different Solid Supports and Ionic Liquids on Synthesis of N-Methyl-C-phenylnitronea
Grinding
Microwaved
Yield (%)
Entry
Solid Support/Base
Ionic Liquidb
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
MgO
Alumina/K2CO3
Molecular sieves (pore size 3 A)/K2CO3
–
–
–
2.5
8
10
12
65
60
60
98
72
61
50
25
30
32
45
55
50
45
60
70
65
˚
Silica gel/K2CO3
–
–
–
–
[bmim]Cl
[bmim]PF6
[bmim]BF4
Abbreviation: bmim, butylmethylimidazolium.
aReactants used: 0.5 mmole of benzaldehyde, 0. 5 mmole of methylhydroxylamine hydrochloride, and 0.5 mmole of base.
bReactants were mixed in 2 mL of ionic liquid.
cIsolated yields after recrystallization.
dComparative experiment under microwave activation 10 min at 80◦C (optimized conditions).
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of Nitrones over MgO under Solvent-Free Conditions 179
R3
R2
O
H
O
+
N
MgO
R3NHOH, HCl
+
R2
H
Grinding
1
3
2
2a: R3=Me, 2b: R3=Phenyl, 2c: R3=t-Butyl
3
2
3
2
3
3f: 4-Methylphenyl, R = Me
3a: R = Phenyl, R = Me
3k: R = 4-Methoxyphenyl, R = Ph
2
3
2
3
2
3
3g: R = 2-Hydroxyphenyl, R = Ph
3b: R = 2-Methoxyphenyl, R = Me
3l: R = 3-Ethoxy-2-hydroxyphenyl, R = t-Butyl
2
3
2
3
2
3
3h: R = 5-Bromo-2-hydroxyphenyl, R = Ph
3c: R = 2-Pyridyl, R = Me
3m: R = 2-Hydroxy-4-methoxyphenyl, R = t-Butyl
2
3
2
3
2
3
3i: R = 2,3-Dihydroxyphenyl, R = Ph
3d: R = 2-Furyl, R = Me
3n: R = 5-Bromo-2-hydroxyphenyl, R = t-Butyl
2
3
2
3
2
3
3j: R = 4-Nitrophenyl, R = Ph
3e: R = 4-Cyanophenyl, R = Me
3o: R = 2-Hydroxy-5-methoxyphenyl, R = t-Butyl
SCHEME 2
TABLE 2 Synthesis of Nitrones by Hand-Grinding over MgO under Solvent-Free Conditions
Melting Point (◦C) Found
Entry
R2
R3
Time (min)
Product
(Lit. [Ref.] Reported, ◦C)
Yield (%)a
1
2
3
4
5
6
7
8
Phenyl
2-Methoxyphenyl
3-Pyridyl
2-Furyl
4-Cyanophenyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
Methyl
Methyl
2.5
3
4.5
5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
83–85 ([10] 83–84)
84–84.5b
74–76 ([10] 75–79)
88–90 ([10] 90)
98
95
89
92
90
91
91
89
94
93
90
87
86
89
87
71
69
3
183–185 ([14] 187)
117–120([11] 118–120)
129–131b
4-Methylphenyl
5.5
4.5
5
5.5
4.5
3.5
6
5.5
6
6
2-Hydroxyphenyl
5-Bromo-2-hydroxyphenyl
2,3-Dihydroxyphenyl
4-Nitrophenyl
4-Methoxyphenyl
3-Ethoxy-2-hydroxyphenyl
2-Hydroxy-4-methoxyphenyl
5-Bromo-2-hydroxyphenyl
2-hydroxy-5-methoxyphenyl
CH3(CH2)2-
173–176b
9
159–161b
10
11
12
13
14
15
16
17
181–183 ([10] 183–184)
113–116 ([10]115–116)
90–92 ([15] 91.9)
13–116 ([15] 115.2–116)
115–118 ([15] 118.7)
69–71 ([14] 70.4–70.6)
Yellow oil
15
12
CH3(CH2)5-
Yellow oil
aIsolated yields after recrystallization.
bSpectroscopic data are shown in the experimental section.
CONCLUSION
Avance AC-400 MHz (or 300 MHz) spectrometer
and 13C NMR spectra at 100 MHz (or 75 MHz)
on the aforementioned instrument. Mass spectra,
using electron ionization (EI)-mass spectrometry
(MS), were recorded on a Shimadzu GCMS-QP-
2000A mass spectrometer. Elemental analyses were
carried out on a Perkin-Elmer 240C elemental ana-
lyzer and are reported in percentage atomic abun-
dance. All melting points are uncorrected and mea-
sured in an open glass capillaries on a Stuart melting
point apparatus.
In conclusion, the present procedure provides a fast
and efficient method for the synthesis of nitrones
on the surface of MgO under solvent-free condi-
tions. The notable advantages of this procedure are
(a) very fast reaction time; (b) mild reaction con-
ditions; (c) general applicability; (d) excellent yields;
and (e) green synthesis avoiding toxic solvents. Thus,
it provides a more practical alternative to the exist-
ing methods.
EXPERIMENTAL
General Information
Preparation of Nitrones in ILs:
General Procedure
All reagents were purchased from the Merck com-
pany and used without further purification. 1H NMR
spectra were obtained in CDCl3 solution on a Bruker
The selected aldehyde (0.2 mmol), monosubsituted
hydroxylamine (2a–2c) (0.2 mmol), and IL (2 ml)
Heteroatom Chemistry DOI 10.1002/hc

180 Valizadeh and Dinparast
were stirred at room temperature for appropriate
time (Table 2). The completion of reaction was mon-
itored by TLC, with EtOAc/petroleum as the eluent.
After the completion of the reaction, the mixture was
extracted with ether. The extracts were concentrated
on a rotary evaporator and the crude mixture was pu-
rified by recrystallization with EtOH/EtOAc to afford
the corresponding nitrones.
7.12 (dd, J = 1.58 Hz and J = 7.59 Hz, 1H), 6.83
(d, J = 7.59 Hz, 1H), 6.75 (d, J = 1.58 Hz, 1H); δC
13C NMR (CDCl3, 75 MHz) 147.54, 147.42, 145.81,
141.30, 130.63, 129.41, 123.23, 121.84, 119.85,
117.73, 115.99; EI-MS [MH]+ m/z 291; Anal. calcd.
(%) for C13H10BrNO2: C, 53.45; H, 3.45; N, 4.79.
Found (%): C, 53.35; H, 3.42; N, 4.68.
C-(2,3-Dihydroxyphenyl)-N-phenyl-nitrone (3i).
IR νmax/cm−1: 3450–3000 (OH), 1569 (C N), 1151
(N O), and 1035 (C O). 1H NMR (400 MHz, CDCl3):
δ 12.40 (s, 1H, OH), 8.00 (s, 1H, nitronyl H), 7.77–
7.75 (m, 2H, ArH), 7.52–7.47 (m, 5H, ArH and OH),
7.30 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.88 Hz, 1H); δC
13C NMR (CDCl3, 100 MHz) 159.04, 145.92, 139.56,
137.07, 134.38, 130.82, 129.46, 122.29, 121.79,
118.70, 110.70; electrospray ionization-MS [MH]+
m/z 230; Anal. calcd. (%) for C13H11NO3: C, 68.11;
H, 4.84; N, 6.11. Found (%): C, 68.05; H, 4.83; N,
6.09.
Preparation of Nitrones over Solid Supports:
General Procedure
The selected aldehyde (0.2 mmol), the monosubsi-
tuted hydroxylamine (2a–2c) (0.2 mmol), and the
solid support (2 g) were cogrinded in a mortar at
room temperature for appropriate time (Table 2).
The completion of reaction was monitored by TLC,
with EtOAc/petroleum as the eluent. After the com-
pletion of the reaction, the mixture was extracted
with CHCl3. The extracts were concentrated on a ro-
tary evaporator and the crude mixture was purified
by recrystallization with EtOH/EtOAc to afford the
corresponding nitrones (Table 2).
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