An efficient and rapid chemoselective synthesis of α-Aryl-N-methylnitrones in dry media

Article abstract of DOI:10.1007/s007060170011

A simple, efficient, and eco-friendly procedure was developed for the condensation of N-methylhydroxylamine hydrochloride with benzaldehydes bearing electron-donating or electron-withdrawing substituents in the presence of powdered molecular sieves (3 A)

Full text of DOI:10.1007/s007060170011

Monatshefte fuÈr Chemie 132, 1547±1549 (2001)
An Ef®cient and Rapid Chemoselective
Synthesis of a-Aryl-N-methylnitrones
in Dry Media
Ã
Mohammad A. Bigdeli and Mir M. A. Nikje
Faculty of Chemistry, Teacher Training University, Tehran, Iran
Summary. A simple, ef®cient, and eco-friendly procedure was developed for the condensation of
N-methylhydroxylamine hydrochloride with benzaldehydes bearing electron-donating or electron-
Ê
withdrawing substituents in the presence of powdered molecular sieves (3 A) in a solventless system.
ꢀ-Aryl-N-methylnitrones are obtained in excellent yields (80±100%); similar aromatic ketones do not
react under these conditions, rendering the method chemoselective.
Keywords. ꢀ-Aryl-N-methylnitrones; Dry media; Chemoselective synthesis; Molecular sieve;
Condensation.
Introduction
There are several methods of preparation of ꢀ-aryl-N-methylnitrones [1±6], all of
them having merits and drawbacks. One disadvantage common to all is that they are
conducted in organic solvents. An ef®cient, mild, and eco-friendly procedure would
therefore be of interest. A literature survey showed no reports on syntheses of ꢀ-
aryl-N-methylnitrones in solventless systems.
Heterogeneous organic reactions have proven useful both in the laboratory and
in industry. In these reactions, the reagents are supported on porous solids. The
advantages of such procedures over conventional solution phase reactions result
from good dispersion of active reagent sites, associated selectivity, and easier work-
up. The recyclability of some of the solid supports renders the processes truly eco-
friendly. In view of the current thrust on solid state synthesis [7] and the emphasis
on green chemistry [8], there is a merit in developing a solventless method for the
preparation of ꢀ-aryl-N-methylnitrones using inexpensive, commercially available
starting materials and non-polluting catalysts.
Condensation of N-methylhydroxylamine hydrochloride with benzaldehydes is
the most common method employed for the synthesis of ꢀ-aryl-N-methylnitrones.
Usually, it is executed in ethanol and requires warming or even re¯ux in most cases
Ê
[1, 6±9]. In this communication we report on the use of molecular sieve (3 A) as a
catalyst for the synthesis of nitrones in a solventless medium.
Ã
Corresponding author. E-mail: mbig@saba.tmu.ac.ir

1548
M. A. Bigdeli and M. M. A. Nikje
Results and Discussion
Ê
The ability of molecular sieve (3 A) to facilitate the reaction of various benzaldehydes
with N-methylhydroxylamine hydrochloride in dry media was demonstrated, and
the resulting data are summarized in Table 1. Aromatic aldehydes with electron-
donating or electron-withdrawing substituents were converted to the corresponding
nitrones in high yields in less than 15 minutes.
Ê
In order to evaluate the in¯uence of molecular sieve (3 A), the reaction of
benzaldehyde and N-methylhydroxylamine hydrochloride without molecular sieve
was also tested. However, the aldehydes remained unchanged after 30 min of
grinding thoroughly in a mortar.
Another important observation is the exclusive reaction of aldehydes with N-
methylhydroxylamine hydrochloride, irrespective of the presence of ketones. When
one equivalent of an aldehyde in the presence of one equivalent of a similar ketone
was treated with two equivalents of N-methylhydroxylamine hydrochloride, only
the aldehyde was selectively converted to the corresponding nitrone, whereas the
ketone did not react at all (Scheme 1).
Ph2CO ꢀ1 equiv:†
Ph2CˆNꢀO†CH3
PhCHˆNꢀO†CH3
PhCH3CˆNꢀO†CH3
0%
100%
0%
‡
‡
CH3NHOH Á HCl ꢀ2 equiv:†
CH3NHOH Á HCl ꢀ2 equiv:†
!
!
PhCHO ꢀ1 equiv:†
PhCH3CO ꢀ1 equiv:†
4-NO2PhCHO ꢀ1 equiv:†
4-NO2PhCHˆNꢀO†CH3 100%
Scheme 1
Therefore, this methodology can be used selectively for the preparation of ꢀ-
aryl-N-methylnitrones of compounds containing both aldehyde and ketone
functionalities.
A wide variety of benzaldehydes with both electron-donating and electron-
withdrawing substituents were treated likewise to give the corresponding nitrones in
high to excellent yields (Table 1). To the best of our knowledge this is the ®rst
Ê
example of molecular sieve (3 A) catalysis of this reaction.
Ê
Table 1. Solventless synthesis of ꢀ-aryl-N-methylnitrones using molecular sieve (3 A)
CH3NHOH Á HCl
ArCHˆO
! ArCHˆNꢀO†CH3
ꢀ
Molecular sieve ꢀ3 A†
1
2
Ar
Melting point/ꢁC
Yield/%
2a
2b
2c
2d
2e
2f
Phenyl
82±84
119±121
89±91
98
92
4-Methylphenyl
2-Furyl
80
2-Nitrophenyl
2-Hydroxyphenyl
2,4-Dimethoxyphenyl
4-Nitrophenyl
4-Chlorophenyl
3-Nitrophenyl
91±94
100
88
141±143
132±135
216±219
127±129
119±122
90
2g
2h
2i
100
84
98

Solid-State Synthesis of ꢀ-Aryl-N-methylnitrones
1549
Experimental
Ê
All benzaldehydes, molecular sieve (3 A), and N-methylhydroxylamine hydrochloride were
purchased from Merck. Compound 2a [9] is known and was characterized by comparision of
melting point and spectroscopic data with those of an authentic sample. For compounds 2b±i, the IR
and NMR spectra are similar to that of compound 2a.
Preparation of ꢀ-phenyl-N-methylnitrones; general procedure
A mixture of N-methylhydroxylamine hydrochloride (1.2 mmol), ®nely powdered molecular sieve
Ê
(3 A) (0.3 g), and benzaldehyde (1.2 mmol) were grinded thoroughly for 10 min. The reaction mixture
was set aside for further 5 min at ambient temperature. To the crude product mixture, 2Â10 cm3
CHCl3 were added, and solid parts were ®ltered off. The solvent was evaporated to dryness, and the
residue was crystallized from petroleum ether (60±80ꢁC) to afford the ꢀ-phenyl-N-methylnitrones.
Acknowledgements
We acknowledge the support of the Teacher Training University for a fellowship and ®nancial
assistance.
References
[1] a) Abou-Gharbia M, Joullie MM (1977) Synthesis 318; b) Abou-Gharbia M, Joullie MM (1979)
Org Prep Proced Int 11: 95
[2] Bimanand AZ, Coates RM (1984) J Org Chem 49: 3127
[3] Patai S, Rappoport Z (1989) Nitrones, Nitronates and Nitroxides. Wiley, New York, and references
cited therein
[4] Shindo H, Umezawa B (1962) Chem Pharm Bull 10: 492; Chem Abstr (1962) 57: 14, 598
[5] Exner O (1955) Collection Czech Chem Commun 20: 202; Chem Abstr (1955) 49: 11, 603
[6] Hamer J, Macaluso A (1964) Chem Rev 29: 473 and references cited therein
[7] Balog M, Laszlo P (1993) Organic Chemistry Using Clays. Springer, Berlin and references cited
therein
[8] a) Tanaka K, Toda F (2000) Chem Rev 100: 1025 and references cited therein; b) Varma RS (1999)
Green Chemistry 1(1): 43 and references cited therein
[9] Koyano K, Suzuki H (1968) Tetrahedron Lett 15: 1859
Received March 26, 2001. Accepted (revised) May 7, 2001